1. Introduction

Microwaves (MW), a form of non-ionizing electromagnetic radiation in the frequency range of 300 MHz to 300 GHz, exhibit physicochemical properties that enable centimeter-scale tissue penetration and efficient coupling with biological dielectrics. These characteristics have established their critical role in a wide range of biomedical applications such as tumor thermal ablation, physical therapy, and non-invasive imaging^[1,2]. In contrast to optical modalities (e.g., photothermal and photodynamic therapies), which are fundamentally confined to superficial depths by strong tissue scattering and absorption^[2,3], or ultrasonic therapies often restricted by acoustic impedance mismatches at bone or air interfaces^[4,5], MWs maintain superior propagation efficiency and spatial uniformity in deep-seated tissues^[1,2,6,7]. Consequently, MW technology has been widely adopted in clinical practice, currently dominated by microwave ablation (MWA) for solid tumors in the liver, lung, and kidney^[8-11], as well as rapid hemostasis and deep-tissue diathermy^[12].

The biological effects of MWs arise from several distinct yet interconnected mechanisms, among which the thermal effect remains the most established^[13,14]. Importantly, the thermal effect represents the macroscopic outcome of electromagnetic energy dissipation via dielectric and magnetic loss processes^[15]. Dielectric loss primarily originates from dipolar rotation and ionic conduction: under an alternating high-frequency electric field, polar molecules, predominantly water, attempt to realign with the oscillating field, but the rapid field reversal induces a phase lag (dielectric relaxation), converting electromagnetic energy into kinetic energy and ultimately into heat through molecular friction^[16]. Magnetic loss, by contrast, involves the conversion of the magnetic component of the MW field into thermal energy via hysteresis loss and eddy current loss, particularly in the presence of magnetic-responsive materials^[17]. Together, these mechanisms enable rapid and volumetric heating that is substantially more efficient than the conductive heating characteristic of radiofrequency ablation^[18,19]. Beyond the dominant thermal effects, specific biomaterials possessing tailored structures and compositions can be excited by MW irradiation to generate reactive oxygen species (ROS), exhibiting a phenomenon analogous to the photodynamic effect known as the microwave-dynamic effect. Therapeutic strategies predicated on this physicochemical mechanism are defined as microwave-dynamic therapy (MDT)^[20,21]. Analogous to photodynamic therapy, MDT utilizes MW energy to activate deep-tissue sensitizers, typically semiconducting heterojunctions or piezoelectric materials, thereby inducing potent non-thermal cytotoxicity^[22,23]. Under MW exposure, the oscillating electric field promotes the separation of electron-hole pairs at material interfaces^[24]. These charge carriers subsequently migrate to the surface and participate in redox reactions, converting local water or oxygen molecules into ROS^[25,26]. This non-thermal therapeutic modality is particularly advantageous for preserving heat-sensitive anatomical structures, such as major blood vessels and peripheral nerves^[27]. In parallel, MW fields exert a significant influence on cellular ion homeostasis^[28]. Accumulating evidence from studies on primary hippocampal neurons and cardiomyocytes suggests that MW exposure can induce both calcium influx and efflux, depending on the field intensity and frequency^[29,30]. Such observations indicate that MW irradiation perturbs the dynamic equilibrium of voltage-gated and ligand-gated ion channels, potentially triggering cellular dysfunction or therapeutically relevant signaling modulation^[31]. In addition to therapeutic applications, MWs serve as a powerful diagnostic modality through microwave-induced thermoacoustic imaging (MITAI)^[32,33]. This technique is based on the thermoelastic expansion mechanism, wherein pulsed MW absorption induces a transient temperature rise, leading to rapid volumetric expansion and the subsequent emission of ultrasonic waves^[34]. By detecting these ultrasound signals, MITAI effectively integrates the high electromagnetic contrast of MW absorption with the spatial resolution of ultrasound imaging, enabling deep-tissue visualization with enhanced sensitivity^[35].

To fully harness the diagnostic and therapeutic potential of microwave medicine, a refined system of energy-tissue interaction is essential, particularly for achieving enhanced precision and greater clinical versatility. For instance, in thermal therapies, a critical objective is to circumvent the physiological heat-sink effect caused by blood perfusion^[10,36,37], thereby ensuring sufficient heating of large tumor masses while preventing collateral damage to healthy tissues. Similarly, advancing MDT requires overcoming the intrinsic barriers of the hypoxic tumor microenvironment and the rapid recombination of charge carriers inherent to low-photon-energy excitations^[3,38,39]. Regarding ion modulation, transforming variable MW-induced fluxes into spatially and temporally selective signaling events is essential to minimize systemic unpredictability^[40,41]. Furthermore, in MW imaging, amplifying the subtle dielectric contrast of early-stage lesions remains a key priority for achieving high-sensitivity detection^[42,43]. The flourishing development of functional biomaterials aligns perfectly with these clinical imperatives, offering a transformative toolkit to bridge these gaps. By engineering high-dielectric or magnetic nanoparticles as localized energy antennas, it becomes possible to manipulate MW absorption patterns, creating steep thermal gradients that strictly define the treatment boundary^[44,45]. To potentiate MDT, biomaterials are being rationally designed through band-gap engineering or the construction of Schottky junctions to suppress charge-carrier recombination, often coupled with oxygen-generating components to sustain ROS production amidst hypoxia^[46]. In the regulation of ionic homeostasis, bioengineered materials can serve as exogenous ion reservoirs. Upon microwave activation, these responsive nanocarriers enable the controlled and localized release of specific ions (e.g., Ca²⁺, Zn²⁺, and Cu²⁺), thereby directly perturbing intracellular ion balance^[47,48]. Moreover, the abundant ROS generated under microwave irradiation can oxidatively modify cysteine residues in calcium channel–associated proteins, leading to channel activation and enhanced Ca²⁺ influx^[49]. In parallel, microwave-induced electromagnetic perturbations may further disrupt membrane potential, synergistically promote calcium overload and amplify ionic imbalance within tumor cells^[41]. For diagnostic precision, contrast agents featuring high thermal expansion coefficients and robust MW absorption cross-sections have been developed, markedly enhancing the signal-to-noise ratio in thermoacoustic detection^[50].

In this review, we provide a systematic overview of how engineered biomaterials modulate microwave-tissue interactions to expand the horizons of microwave medicine. We specifically focus on the physicochemical mechanisms, ranging from dielectric heating and magnetic loss to catalytic ROS generation and ionic regulation, that enable biomaterials to amplify or redirect microwave energy for targeted interventions. The discussion is categorized into major therapeutic domains, including antitumor, antibacterial, and anti-inflammatory strategies, alongside diagnostic innovations in microwave imaging and emerging frontiers such as tissue repair and neuromodulation. By correlating material design parameters with biological outcomes, we aim to clarify the design principles for next-generation microwave-responsive platforms and critically analyze the challenges facing their translation from bench to bedside (Scheme 1).

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Scheme 1. Engineering biomaterials for microwave medicine: Physicochemical mechanisms and emerging biomedical applications. ROS: reactive oxygen species; MW: microwave; RA: rheumatoid arthritis.

2. Biomaterial-Sensitized Tumor MWA

Among the various biomedical applications of microwave medicine, antitumor therapy represents one of the earliest and currently most intensively investigated directions involving biomaterials. This is mainly because, although microwave-based treatments possess notable physical advantages for the intervention of deep-seated tumors, their ability to precisely control local energy deposition and modulate subsequent biological effects remains insufficient to meet the practical demands of tumor therapy^[51]. By introducing material systems with specific dielectric, electromagnetic, or biological functional properties, researchers have sought to reshape microwave energy deposition and the associated biological responses within tumor regions, without markedly increasing the external power burden. This approach aims to improve therapeutic efficiency while reducing the risk of side effects^[52]. Toward this goal, biomaterial-assisted microwave antitumor strategies have gradually evolved from the simple enhancement of thermal effects to more comprehensive, multi-level approaches that integrate non-thermal effects and the regulation of post-treatment biological processes.

In early studies, biomaterials were introduced into microwave-based antitumor systems mainly to enhance local microwave hyperthermia or ablation effects. A large body of evidence has demonstrated that materials with high dielectric constants or pronounced dielectric loss properties, such as ionic liquids (ILs), carbon-based materials, and magnetic materials, can significantly increase energy absorption efficiency in tumor regions under microwave irradiation. As a result, effective tumor suppression can be achieved at lower power levels or with shorter irradiation times^[53-56]. Such strategies have been widely applied in MWA and localized hyperthermia settings, where they help to alleviate issues related to non-uniform energy distribution and poorly defined ablation margins, and have shown consistent therapeutic outcomes across various tumor models. For example, in early work by Meng’s group, silica nanoparticles with or without a gold core were used as templates to synthesize hollow polydopamine (PDA) nanoparticles loaded with specific ILs. These particles (ILs/PDA) were introduced into the tumor site and served as a microwave-sensitive medium. This system markedly enhanced local temperature elevation and tumoricidal efficacy during microwave hyperthermia, and demonstrated favorable antitumor performance in tumor models^[57] (Figure 1A,B,C).

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Figure 1. Application and mechanism of biomaterials in microwave tumor therapy. (A) TEM images of (1) SN; (2) SN/PDA core/shell nanoparticles; (3) hollow PDA nanoparticles and (4) ILs/PDA nanocomposites; SEM images of (5) SN; (6) SN/PDA core/shell nanoparticles; (7) hollow PDA nanoparticles and (8) ILs/PDA nanocomposites. The insets are SEM images with higher magnifications. The size distributions of (9) SN; (10) SN/PDA core/shell nanoparticles; (11) hollow PDA nanoparticles and (12) ILs/PDA nanocomposites; (B) Near infrared thermal imaging of ICR mice bearing H22 tumors under microwave treatment for 5 min at 1 min intervals; (C) The curves of relative tumor weight (1) and tumor volumes (2) in the different treatment groups. (* denotes statistical significance for the comparison of other groups, *P < 0.05). Republished with permission from^[57]; (D) Preparation of AIEgen-engineered bioactive mitochondria and their application for microwave-dynamic cancer therapy; (E) Healthy Mito@DCPy transplants not only downregulate the Bcl-2 overexpression on their own but also enhance the treatment effect of ROS production by MW irradiation, making the therapeutic efficiency of MDT more synergistic. Republished with permission from^[58]; (F) Synthesis of BMCPH nanoparticles and a schematic diagram of BMCPH for mediating tumor MWTT and reactivating the antitumor immune effect; (G) CD8⁺ T cells in distant tumors and spleen tissues; (H) Metastatic tumor formation in the lung. Republished with permission from^[67]. TEM: transmission electron microscopy; SN: silica nanoparticles; PDA: polydopamine; ILs: ionic liquids; SEM: scanning electron microscope; ICR: Institute of Cancer Research; GLUT1: glucose transporter 1; MDT: microwave-dynamic cancer therapy; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; MW: microwave; BMCPH: Bi-MOF@L-Cys@PEG@HA; MWTT: microwave thermal therapy; DCPy: mitochondrial-targeting aggregation-induced emission luminogens.

Building on thermal enhancement strategies, some studies have further explored the antitumor potential of microwave therapy under non-ablative or mild-temperature conditions. By introducing biomaterials with catalytic or electromagnetic-responsive properties, microwave irradiation can induce the generation of ROS, thereby triggering oxidative stress and apoptotic responses in tumor cells. Compared with conventional high-temperature ablation, this microwave dynamic therapy modality achieves significant antitumor efficacy while maintaining a relatively low temperature rise, indicating a potential advantage in reducing heat-related side effects. For example, Ben’ group screened a mitochondrial-targeting microwave sensitizer (mitochondrial-targeting aggregation-induced emission luminogens (DCPy)) from a photosensitizer library and integrated it with mitochondria through non-covalent interactions to construct a bioactive microwave sensitizer (Mito@DCPy)^[58] (Figure 1D,E). This material not only generates ROS under microwave irradiation to induce apoptosis of cancer cells in deep tissues, but also enhances the efficacy of non-thermal microwave therapy by restoring oxidative phosphorylation and reprogramming cancer cell metabolic pathways.

Furthermore, in recent years, there has been an increasing number of studies attempting to apply the combined effects of microwave thermal and non-thermal effects to tumor treatment in order to enhance the local tumor-killing effect^[59-61]. Inspired by the combined application strategies of various anti-tumor methods such as photodynamic therapy and chemotherapy, biomaterial-mediated microwave therapy has gradually been introduced and integrated into the design of other mature treatment methods^[62-66]. Considering that residual tumor tissues after incomplete MWA may induce immunosuppression and thereby increase the risks of tumor recurrence and metastasis, a recent study constructed a microwave-responsive bismuth-based metal-organic framework (MOF) nano-immunomodulatory system (Bi-MOF@L-Cys@PEG@HA, BMCPH)^[67]. During microwave hyperthermia, this system simultaneously enabled tumor ablation, ROS scavenging, and H₂S-responsive release, thereby reversing immunosuppression induced by incomplete ablation and activating antitumor immune responses. As a result, tumor recurrence and metastasis were effectively suppressed (Figure 1F,G,H). This strategy demonstrates that the introduction of biomaterials can not only enhance the local tumoricidal effects of microwave therapy, but also regulate the tumor immune microenvironment during the post-treatment stage. Such systemic-level modulation helps reduce the risks of recurrence and metastasis, and provides new insights for improving the overall efficacy of microwave-based antitumor therapies.

In summary, the introduction of biomaterials into microwave-based antitumor therapy has shifted microwave action from reliance on local temperature elevation as a single physical parameter to a treatment process that can be regulated at multiple levels through material design. By modulating the manner in which microwave energy is deposited within tumor regions and coupling this process with biological effects such as oxidative stress or immune regulation, biomaterials have significantly expanded the controllable space of microwave antitumor therapy in terms of therapeutic efficacy, safety, and long-term tumor control. These studies indicate that rational material design is a critical foundation for driving the transition of microwave therapy from single energy-based action to controllable biological effects.

3. Microwave Antimicrobial Strategies

Bacterial infections, particularly those involving deep tissues and drug-resistant pathogens, remain a major challenge in current clinical practice. Conventional antibiotic therapies not only face the problem of rapidly increasing antimicrobial resistance, but also suffer from limited effective accumulation at local infection sites due to tissue barriers and microenvironmental constraints^[68]. To address the antimicrobial resistance crisis, alternative strategies that are antibiotic-free or capable of enhancing antibiotic efficacy, such as phototherapy, have been actively explored. However, the limited penetration depth of near-infrared light restricts these approaches to the treatment of superficial wound infections^[69], making them unsuitable for deep tissue infections. In recent years, MWs have attracted increasing attention for antibacterial applications because of their strong tissue penetration and high energy transfer efficiency^[70].

In the context of food safety, microwave irradiation can inactivate bacteria through thermal effects. However, when microwave hyperthermia is directly applied to antibacterial treatment, prolonged microwave exposure may cause excessive heating and inevitably result in thermal injury to normal tissues, thereby limiting its application in infection control^[71]. To address this issue, researchers have introduced materials with specific electromagnetic functions, as well as bacteria-targeting materials capable of controlled antibiotic release. These approaches enhance the local efficiency of microwave action at infection sites and allow for reduced microwave dosage or temperature elevation. When combined with chemotherapy, they enable more effective and controllable antibacterial outcomes. For example, the group of Wu Shuilin proposed a microwave-assisted antibacterial strategy that integrates material-based targeting with magnetic targeting advantages^[72]. By constructing a microwave-responsive Fe₃O₄/carbon nanotubes (CNTs)/gentamicin (Fe₃O₄/CNT/Gent) nanocomposite system, this system enabled precise capture of methicillin-resistant Staphylococcus aureus (MRSA) in deep tissues, mild localized heating, bacterial membrane disruption, and synergistic drug release. As a result, the system effectively suppressed MRSA dissemination along blood vessels and achieved efficient bacterial clearance, demonstrating broad potential for the treatment of osteomyelitis and other deep-seated bacterial infections (Figure 2A,B,C,D).

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Figure 2. Application and mechanism of biomaterial enhanced microwave antibacterial. (A) The schematic illustration of the MCCT of Fe₃O₄/CNT/Gent (Fe₃O₄/carbon nanotubes/gentamicin); (B) Representative SEM observation of Fe₃O₄/CNT/Gent binding to MRSA; (C) Wright-stained images of infected bone marrow tissue after 14 days of treatment. Scale bars = 20 μm; (D) The MRSA counts in the infected bone marrow after 2 days with different treatments^[72]; (E) Schematic illustration of MW-actuated hot-carrier/polarization triggers catalysis coordinating Staphylococcus aureus ribosome stalling against various deep-seated infections; (F) Volcano plot of different gene expression levels in S. aureus after MW treatment; (G) KEGG enrichment analysis of all differential genes in the top 10; (H) Quantitative analysis of metabolites in the activated pathways. Data are presented as mean ± standard deviation from a representative experiment (n = 6 independent samples; p-values were analyzed by t-test.). Republished with permission from^[73]; (I) Typical TEM image of the GNs. Scale bar, 50 nm. Insert: the particle size distribution of GNs; (J) The chemical compositions of GNs and the ratio of each component; (K) SEM images representing the morphologies and structures of S. aureus after GNs treated different time. Scale bar, 0.5 μm; (L) SEM images representing the morphologies and structures of E. coli before and after different treatments. Scale bar, 2 μm. Representative TEM images of E. coli treated with GNs under MV excitation for 15 min or not. Scale bar, 0.5 μm and 100 nm (enlarged view)^[76]. MCCT: microwaveocaloric-chemotherapy; CNT: carbon nanotube; SEM: scanning electron microscope; MRSA: methicillin-resistant Staphylococcus aureus; MW: microwave; KEGG: The Kyoto Encyclopedia of Genes and Genomes; TEM: transmission electron microscopy; GNs: Garcinia nanoparticles; MV: microwave; E. coli: Escherichia coli.

However, the long-term use of antibiotics still faces the problem of drug resistance. Therefore, combining microwave hyperthermia with microwave dynamic therapy represents a promising approach^[14]. A recent study proposed a microwave-driven energy translation and amplification strategy, in which microwave thermal effects are coupled with thermoelectric or pyroelectric processes to significantly enhance non-thermal antibacterial effects^[73]. Specifically, researchers combined microwave-sensitive CNTs with thermoelectric materials (Bi₂Te₃) or pyroelectric materials (ZnO) to construct a microwave–thermal–electric tandem reactor (CNTs-Bi₂Te₃ or CNTs-ZnO). Under microwave irradiation, the CNTs first convert microwave energy into a local heat source, which subsequently activates carrier migration or polarization in the adjacent materials, efficiently inducing the generation of ROS for the treatment of deep bacterial infections. Further transcriptomic and metabolomic analyses revealed that the microwave-assisted system significantly inhibits bacterial ribosomal function, thereby blocking protein synthesis and proliferation at the molecular level (Figure 2E,F,G,H). This multi-level mechanism allows microwave-based antibacterial therapy to no longer rely solely on local high temperature, but to achieve a substantially amplified bactericidal effect through material-mediated energy translation and biological pathway regulation. This strategy provides new insights for the application of microwave technology in the treatment of deep-seated infections. Moreover, considering biofilms as a critical barrier limiting antibacterial efficacy, recent studies have demonstrated that microwave-responsive nanomaterial systems exhibit significant advantages in biofilm disruption. For instance, Fe₃O₄/CuS/Emodin nanoparticles can penetrate Staphylococcus aureus biofilms via enzyme-mediated affinity interactions and, under microwave irradiation, generate synergistic thermal effects and ROS, leading to effective destruction of the extracellular polymeric substance matrix and eradication of embedded bacteria. Such strategies have achieved substantial biofilm removal and high bactericidal efficiency^[74]. These findings suggest that microwave-assisted material systems not only enhance the killing of planktonic bacteria but also overcome the biofilm barrier, enabling efficient intervention in refractory infections.

In addition to material-mediated energy conversion for amplifying microwave antibacterial effects, the direct regulatory effect of microwave electromagnetic fields on bacterial structures has also received increasing attention. Gram-negative bacteria possess an asymmetric outer membrane composed of lipopolysaccharides (LPS) and phospholipids, which acts as a low-permeability barrier and significantly restricts the transmembrane entry of many antibacterial agents and nanomaterials^[75]. Based on the high sensitivity of numerous polar molecules in the outer membrane to alternating electric fields, a recent study proposed using MWs as an external physical tool to disrupt the asymmetric outer membrane of Gram-negative bacteria and promote drug entry^[76]. The study demonstrated that under microwave irradiation, LPS and phospholipid molecules in the outer membrane undergo continuous orientation rearrangement in response to the alternating electric field, inducing local structural disorder and weakening membrane integrity. This process generates transient pores that facilitate the entry of nanoparticles. Based on this mechanism, researchers developed Garcinia nanoparticles, originally a narrow-spectrum antibacterial system effective only against Gram-positive bacteria. Under microwave assistance, these nanoparticles were successfully delivered into Escherichia coli cells and completely eradicated bacterial pneumonia caused by mixed Gram-negative and Gram-positive infections in an in vivo model (Figure 2I,J,K,L). This work indicates that the synergistic use of biomaterials and MW can not only enhance bactericidal efficacy but also expand the antibacterial spectrum by modulating bacterial structural barriers, providing a new strategy for non-antibiotic treatment of complex deep infections.

Overall, the introduction of biomaterials has significantly expanded the dimensionality and regulatory scope of microwave-based antibacterial therapy. On one hand, by enhancing microwave absorption, enabling targeted accumulation, or constructing multi-level energy translation pathways, materials can amplify local bactericidal effects under relatively low temperature elevations. On the other hand, the synergistic interaction between MWs and materials can further modulate critical bacterial structures and functional pathways, such as regulating membrane permeability, inhibiting protein synthesis, or disrupting biofilm formation^[77], thereby overcoming the limitations of conventional antibacterial strategies in treating deep infections and drug-resistant pathogens. These studies indicate that microwave antibacterial therapy is no longer confined to a single physical inactivation mode, but is evolving into a comprehensive treatment strategy mediated by biomaterials that integrates both physical and biological mechanisms, providing an important foundation for the development of non-antibiotic and precise infection therapies.

4. Microwave-Mediated Inflammation Modulation

In contrast to infectious inflammation that is primarily driven by pathogen clearance, autoimmune inflammation and tissue injury-associated inflammation are characterized by disrupted immune homeostasis and sustained amplification of inflammatory responses^[78]. In such pathological processes, simple suppression of inflammatory mediators is often insufficient to achieve long-term therapeutic efficacy. Instead, reshaping the local inflammatory microenvironment and guiding immune responses toward the restoration of tissue homeostasis has become a key therapeutic goal. Microwave therapy can improve blood and lymphatic circulation, enhance local oxygen supply, and promote the absorption and dissipation of pathological metabolites. These effects can rapidly alleviate or resolve tissue edema and reduce excessive proliferation of inflammatory cells, which has led to growing clinical interest in microwave-based anti-inflammatory treatment^[79]. Notably, MWs can penetrate cartilage and bone tissues at pathological sites of autoimmune inflammation, such as rheumatoid arthritis (RA), offering a unique advantage over other hyperthermia-based therapies^[14]. In addition, microwave non-thermal effects can enhance structural protein rearrangement and promote transmembrane transport, thereby facilitating the uptake of nanoparticles and drugs. The introduction of biomaterials provides effective amplification and targeting strategies for microwave-mediated immunomodulation, enabling new potential for anti-inflammatory therapy^[80].

Autoimmune inflammation, such as RA, is currently treated in clinical practice mainly with glucocorticoids, nonsteroidal anti-inflammatory drugs, or biological agents. Although these therapies can alleviate symptoms in the short term, long-term use often leads to systemic side effects and provides limited regulation of the local inflammatory microenvironment, making it difficult to achieve a fundamental restoration of immune homeostasis^[81,82]. To overcome these limitations, the integration of biomaterials with microwave technology offers a new therapeutic strategy. Microwave non-thermal effects can modulate tissue redox states and influence immune cell behavior, but their effects are generally weak and lack selectivity. The introduction of microwave-responsive functional materials enables localized amplification and spatiotemporal control of immunomodulation, thereby allowing precise regulation of the inflammatory microenvironment. For example, Chen et al. designed a UiO-66-NH₂@Mn₃O₄/Mn-EGCG@HA nanoplatform that undergoes structural disassembly in the acidic synovial microenvironment of RA under microwave stimulation^[83]. This process releases components with antioxidant and immunoregulatory functions. Meanwhile, endogenous hydrogen peroxide induces the decomposition of Mn₃O₄, which synergistically scavenges ROS and generates oxygen, thereby alleviating local hypoxia. With the assistance of microwave non-thermal effects, the expression of HIF-1α in inflamed tissues is reduced, pro-inflammatory M1 macrophages are reprogrammed toward the anti-inflammatory M2 phenotype, and the secretion of inflammatory cytokines is suppressed. As a result, a systematic remodeling of the local inflammatory microenvironment is achieved (Figure 3A,B,C). Furthermore, another study also demonstrated that the microwave-responsive nanosystem can achieve immune intervention by regulating the redox homeostasis. The functional nanomaterials constructed in this work (UiO-66-NH₂/CeO₂/Cel@HA) can efficiently regulate the level of ROS under microwave action, alleviate oxidative stress, and induce macrophages to transform from an inflammatory phenotype to an anti-inflammatory phenotype, thereby inhibiting the release of inflammatory factors and improving the progression of joint inflammation. This result further proves that the microwave-assisted material system not only can be used as a physical stimulation method, but also can be an important medium for regulating the immune microenvironment, achieving precise intervention of the inflammatory response^[79].

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Figure 3. Biomaterial enhanced microwave-mediated inflammation regulation. (A) Schematic illustration of the fabrication procedures and in vivo therapeutic mechanism of UMnEH (UiO-66-NH₂@Mn₃O₄/Mn-EGCG@HA) against RA; (B) Fluorescence images of O₂ level in the LPS-induced RAW 264.7 cells with different treatments for 24 h (Scale bar: 20 μm). Fluorescence images of HIF-1α level in the LPS-induced RAW 264.7 cells with different treatments for 24 h (Scale bar: 25 μm); (C) The CLSM images of LPS-induced RAW 264.7 cells incubated with UMnEH@Cy7 for different times (0, 2, 4, and 6 h, Scale bar: 20 μm). Republished with permission from^[83]; (D) Effectiveness of microwave therapy combined with Berberine/GelMA via COX-2/IL-1β pathway to treat skeletal muscle injury: An in vivo study in rats; (E) The expression levels of IL-1β, PGE2 in the serum of SD rats in each group at 1/4/7 days after modeling; (F-H) Expression levels of IL-1β, COX-2 in skeletal muscle of SD rats in each group. (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001); (I) Demonstration of modeling effects of soft tissue injury in different groups of SD rats^[86]. RA: rheumatoid arthritis; LPS: lipopolysaccharides; HIF: hypoxia-inducible factor; CLSM: confocal laser scanning microscopy; COX-2: cyclooxygenase-2; IL-1β: interleukin-1β; PGE2: prostaglandin E2; SD: Sprague-Dawley.

In addition to the pathological inflammatory conditions described above, skeletal muscle injury is also an important target for anti-inflammatory therapy. Skeletal muscle injury is often accompanied by persistent pain, limited mobility, and impaired tissue function. The post-injury inflammatory response is characterized by infiltration of neutrophils and macrophages, along with sustained high expression of pro-inflammatory mediators such as tumor necrosis factor-α, interleukin-1β (IL-1β), and prostaglandin E2 (PGE2)^[84]. Current treatments mainly rely on rest, cryotherapy, or nonsteroidal anti-inflammatory drugs. However, these approaches have limited capacity to regulate the local inflammatory microenvironment and to promote rapid tissue repair, while long-term pharmacological intervention may induce systemic side effects^[85]. To improve local inflammation control and repair efficiency, researchers have explored the combination of microwave therapy with biomaterials, in which materials are activated by microwave irradiation to achieve inflammation modulation and controlled drug release^[86]. Specifically, a microwave-responsive hydrogel platform (berberine (BBR)/methacrylate-modified gelatin (GelMA)) was constructed by loading the anti-inflammatory drug BBR into GelMA. Under microwave irradiation, localized heating of the hydrogel promoted BBR release, while microwave non-thermal effects further enhanced local immune cell responses. This strategy significantly reduced the levels of IL-1β, cyclooxygenase-2, and PGE2 in injured skeletal muscle, suppressed pro-inflammatory responses, and promoted macrophage polarization from the M1 to the M2 phenotype. As a result, inflammation resolution and muscle regeneration were accelerated (Figure 3D,E,F,G,H,I).

In summary, microwave-responsive biomaterials have demonstrated substantial therapeutic potential in both autoimmune inflammation and tissue injury–associated inflammation. Through the synergistic interaction between microwave non-thermal effects and material functionalities, this system enables precise regulation of immune cell phenotypes, and improvement of local hypoxia, while also allowing controlled release of drugs or bioactive components. As a result, the inflammatory microenvironment can be systematically remodeled, and excessive inflammatory responses are suppressed. This strategy balances local precision with systemic regulatory capacity, addressing key limitations of conventional pharmacological treatments in terms of targeting specificity, therapeutic durability, and side effects. Moreover, it provides a scalable and versatile platform for the clinical management of chronic autoimmune diseases and trauma-related inflammation, thereby opening new avenues for the application of microwave medicine in anti-inflammatory therapy.

5. Nano-Contrast Agents for Microwave Imaging

As microwave medicine gradually evolves from empirical treatments toward precision and individualized therapy, achieving accurate lesion localization and visualized monitoring of the treatment process has become a critical challenge limiting its further clinical application. The dielectric differences between normal and pathological tissues, such as tumors, provide the basis for microwave imaging. By measuring the scattered microwave field generated by a material, its dielectric constant distribution can be obtained, which forms the goal of microwave imaging^[87,88]. However, the limited intrinsic dielectric contrast of biological tissues, the difficulty of precisely locating small lesions, and the relatively immature imaging systems pose significant challenges for single-modality microwave imaging in accurately identifying complex lesions and guiding microwave therapy^[89-91]. In recent years, biomaterials with microwave-responsive properties have been introduced into imaging systems. By amplifying local microwave energy deposition signals and coupling with multimodal imaging techniques, they provide a new strategy for constructing integrated imaging, guidance, therapy, and feedback microwave diagnostic and therapeutic platforms.

On one hand, some microwave-absorbing materials inherently possess magnetic properties or high atomic number characteristics, making them naturally compatible with clinical imaging modalities such as magnetic resonance imaging (MRI) and computed tomography, thereby enabling lesion localization and therapy guidance. For example, a recent study constructed manganese-doped titanium metal-organic framework (Mn-Ti MOFs) nanosheets via an in-situ doping strategy for microwave treatment of liver cancer^[92]. In situ Mn doping not only introduced crystal defects and narrowed the bandgap of Ti MOFs, enhancing electron-hole separation efficiency, but also endowed the material with excellent T₁-weighted MRI capability. In vitro experiments showed that as Mn concentration increased from 0 to 1.5 mM, the T1 signal of Mn-Ti MOFs@PEG dispersions significantly increased, with longitudinal and transverse relaxation rates (r₁ and r₂) of 2.77 and 6.41 mM^-1 s^-1, respectively, and an r₂/r₁ ratio of 2.315, close to that of commercial Gd-DTPA (2.38), indicating good MRI contrast potential. Further in vivo imaging in a subcutaneous liver cancer mouse model showed that T₁-weighted MR images exhibited clear tumor enhancement after injection of Mn-Ti MOFs@PEG, confirming that the nanosheets could achieve tumor localization and dynamic imaging in vivo (Figure 4A,B,C,D). Combined with microwave therapy, this material not only enables precise targeted ablation but also allows real-time monitoring of therapeutic efficacy via MRI, significantly reducing damage to surrounding normal tissues and providing a reliable experimental basis for microwave-mediated visualized precision antitumor therapy.

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Figure 4. Biomaterial enabled microwave imaging and diagnosis. (A) Schematic images for the synthesis process of Mn-Ti MOFs@PEG nanosheets for MR imaging and MWDT-MWTT; (B) T₁-weigthed MR images in vitro; (C) r₁ and r₂ (relaxation rate and transverse relaxation rate) values; (D) T₁-weigthed MR images of Mn/Ti MOF-PEG in vivo^[92]; (E) Schematic illustration of the synthesis process and therapeutic effects of Gd/MPC^[51]; (F) Schematic illustration of the thermoacoustic imaging in vivo. Republished with permission from^[93]. Mn-Ti MOFs: manganese-doped titanium metal-organic framework; PEG: polyethylene glycol; MR: magnetic resonance; MWDT-MWTT: microwave dynamic-thermal therapy; Gd/MPC: Gd-MOF@aPD-1@CM; CM: change material; NPs@CDDP: cisplatin nanocapsules.

On the other hand, materials may exhibit imaging capabilities under microwave excitation. Cui et al. designed a Gd-based metal-organic framework (Gd-MOF) system. PD-1 inhibitor (aPD-1) was initially loaded in the porous Gd-MOF (Gd/M) system, and then phase change material (PCM) and the cancer cell membrane were further sequentially modified on the surface of Gd/MP to obtain Gd-MOF@aPD-1@CM (Gd/MPC)^[51]. Abundant electronic energy levels and a large number of energy level transitions in electronic configurations make Gd/MPC have extremely strong heating performance. Under microwave irradiation Gd/MPC will be heated to 50 °C in 10 minutes, providing thermal real-time guidance for microwave hyperthermia. (Figure 4E). The traditional imaging methods based on optical signals are prone to be affected by scattering and attenuation in biological tissues, which limits their application in deep lesions. In contrast, the high penetration ability of MW provides potential for deep tissue imaging. Of particular interest, microwave photoacoustic imaging integrates the high contrast of MW with the high resolution of ultrasound. This method relies on microwave-induced local heating to trigger thermoelastic expansion in tissues, generating acoustic signals that can be detected by ultrasound sensors, processed, and reconstructed into images^[33]. For example, a recent study developed cisplatin (CDDP) nanocapsules (NPs@CDDP) with microwave-responsive properties, serving both as contrast agents for emerging photoacoustic imaging and sensitizers for microwave-augmented chemotherapy^[93]. After enzymatic degradation in the tumor microenvironment, NPs@CDDP release L-arginine and CDDP. L-arginine, as a polar molecule, exhibits excellent microwave absorption and acts as a thermosensitive agent and photoacoustic imaging contrast, accurately delineating tumor boundaries and significantly elevating local temperature (Figure 4F,G). In combination with CDDP, this process promotes lipid peroxidation and markedly enhances the efficacy of microwave hyperthermia chemotherapy.

Recent advances in MITAI have significantly improved deep-tissue visualization by combining microwave contrast with acoustic resolution^[94,95]. However, conventional MITAI primarily relies on uniform illumination and scalar energy deposition, which limits its ability to resolve sub-organ structures within complex biological tissues. Reconstruction algorithms, system design, and signal acquisition remain factors that limit the quality, signal-to-noise ratio, and resolution of microwave thermoacoustic imaging, and these limitations are particularly prominent in complex biological tissues with multi-layered structures and high heterogeneity^[96,97]. To overcome this limitation, Wang et al. proposed an electric vector–adapted thermoacoustic computed tomography (EV-TACT) strategy, in which microwave illumination with different polarizations is employed to selectively enhance energy coupling to tissue structures with specific orientations^[98]. By explicitly considering the propagation behavior and polarization characteristics of MW in biological tissues, EV-TACT effectively amplifies thermoacoustic signal excitation from anisotropic sub-organ features, thereby improving the signal-to-noise ratio and revealing structures that are otherwise obscured in conventional MTAT. Notably, EV-TACT enabled label-free, high-contrast imaging of nerve fiber bundles in the brain and dynamic vascular structures in the abdomen of live mice, demonstrating its potential for resolving fine structural and functional information in deep tissues. This work highlights that, beyond material-assisted contrast enhancement, precise regulation of microwave field parameters, such as electric vector orientation, represents a powerful and complementary strategy for improving imaging specificity and spatial resolution in microwave-based biomedical imaging.

Overall, the introduction of biomaterials is driving the evolution of microwave medicine from one-way treatment toward a diagnostic and therapeutic system. Real-time imaging enables acquisition of lesion information and energy deposition distribution, allowing dynamic adjustment of microwave treatment parameters. Post-treatment imaging feedback can further provide objective assessment of therapeutic efficacy and tissue response, supporting more precise and individualized treatment decisions. Looking forward, with the further development of smart responsive materials, multimodal imaging technologies, and microwave devices, integrated platforms that combine imaging guidance, therapy enhancement, and efficacy feedback are expected to become a key direction in microwave medicine, laying a foundation for its clinical translation and standardized application.

6. Emerging and Unconventional Applications

Beyond anticancer, antibacterial, anti-inflammatory therapies, and imaging applications, the integration of MW and biomaterials has also shown exploratory potential in emerging biomedical fields, such as tissue repair and neural modulation. In tissue regeneration and wound healing, microwave therapy has been reported to significantly accelerate wound closure in diabetic mice by enhancing granulation tissue formation, collagen remodeling, and myofibroblast activation^[99]. By incorporating biomaterials with controllable thermal conductivity and microwave responsiveness, microwave energy can be precisely regulated, thereby promoting tissue repair while minimizing thermal damage. Zhang from Taiyuan University of Technology developed a Fe₃O₄@AIPH (2,2-Azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride; AIPH) microneedle patch. The Fe₃O₄@AIPH core-shell nanoparticles were fabricated by a self-assembly method and then loaded on hyaluronic acid microneedle patches^[100]. The microwave absorption characteristics of Fe₃O₄ and the thermal sensitivity of AIPH, combined with the cross-linking and anti-inflammatory effects of lauric acid, were used to achieve multi-effect synergy. Under microwave irradiation, Fe₃O₄ converts electromagnetic energy into thermal energy, triggering AIPH cleavage to produce nitrogenous free radicals (RN·), and enhancing ROS generation capacity of Fe₃O₄, which damages bacterial cell membrane and glutathione transferase function through the synergistic effect of heat, RN· and ROS. At the same time, the released Fe²⁺ and lauric acid induce the polarization of macrophages to M2 type, realizing the dual effect of antibacterial and anti-inflammatory, thereby promoting the proliferation of fibroblasts and collagen secretion, and accelerating the healing of diabetic infected wounds (Figure 5A,B,C). Further studies demonstrated that microwave therapy could facilitate diabetic wound healing by activating the IL-33/ST2 signaling pathway, promoting M2 macrophage polarization, and improving the wound microenvironment^[99].

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Figure 5. Biomaterials expand the novel and unconventional applications of microwave medicine. (A) The schematic diagram of the preparation of Fe₃O₄@AIPH microneedle patches and the mechanism of promoting the healing of diabetic infected wounds; (B) SEM and EDS mapping images of Fe₃O₄@AIPH microneedle patch (Scale bar = 500 μm, 100 μm); (C) Representative images of the effect of each treatment group on promoting wound healing within 10 days (Scale bar = 1 cm)^[100]; (D) (1-8) Microwave inhibits neuronal activity via a nonthermal mechanism; (E) Inter-spike interval for 10 s before and after treatment in sham mice, direct microwave treatment, and microwave SRR treatment; the solid line represents data mean and the box represents SD; statistical significance was calculated using a paired sample t-test where *P < 0.05; (F) Percent change in spike amplitude for 10 s after microwave treatment in sham mice, direct microwave mice, and microwave SRR mice; the solid line represents data mean and whiskers represent SD; statistical significance was calculated using a two-sample t-test where ***P < 0.001; (G) Control brain tissue and brain tissue after three microwave treatments stained with H&E (Scale bar = 100 μm)^[101]. SEM: scanning electron microscope; EDS: energy dispersive X-ray spectroscopy; SRR: split-ring resonator; SD: standard deviation; AIPH: 2,2-Azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride.

In addition to tissue repair, the potential application of MW in the field of neural modulation has also attracted increasing attention in recent years. As a non-ionizing form of energy capable of penetrating the skull, MWs provide a possible approach for deep neural modulation. One study employed a microwave-enhanced electromagnetic structure and designed a split-ring resonator (SRR), which enabled the suppression of abnormal neuronal firing under microwave excitation^[101]. In both in vitro and in vivo epilepsy models, this strategy significantly reduced neuronal calcium spike rate while maintaining local temperature elevation within a safe threshold, thereby demonstrating effective neural inhibition and high spatial precision (Figure 5E,F,G,H). Furthermore, it has been reported that low-intensity microwave electromagnetic fields can directly activate voltage-gated calcium channels, leading to a transient increase in intracellular Ca²⁺ levels and subsequent physiological responses^[102].

Overall, microwave-responsive biomaterials for tissue repair and neural modulation are still at the proof-of-concept and early exploratory stages. Their underlying mechanisms, long-term safety, and capacity for precise regulation require further investigation. Nevertheless, these studies expand microwave medicine from conventional therapeutic ablation toward functional modulation, and provide important insights for its application in broader biomedical contexts.

As mentioned above, microwave therapy is a promising treatment strategy that can be applied in various biomedical applications (Table 1).

7. Conclusions and Future Perspectives

In summary, microwave medicine is evolving from conventional macroscopic thermal therapy toward a mechanism-driven paradigm enabled by engineered biomaterials. By tailoring dielectric and magnetic losses, band structures, and polarization properties, these materials allow precise modulation of microwave–tissue interactions at the micro- and nanoscale. Such designs expand microwave functionality beyond bulk heating, enabling localized energy concentration, microwave-induced ROS generation, and regulation of ionic homeostasis. Through these mechanisms, biomaterial-assisted microwave systems have demonstrated versatile therapeutic capabilities across antitumor, antibacterial, and anti-inflammatory applications, while also advancing high-resolution thermoacoustic imaging. Collectively, these developments establish a unified framework in which materials act as active mediators of electromagnetic energy transduction, facilitating controlled and multifaceted biological regulation.

Future development is expected to move beyond enhancing a single effect toward multifunctional integration and coordinated regulation. Disease-associated microenvironments often involve simultaneous changes in redox balance, energy metabolism, immune responses, and tissue structure. Relying solely on thermal effects or a single type of active species is unlikely to achieve optimal intervention. By rationally designing material composition and structure, it is possible to integrate microwave absorption, energy translation, biological modulation, and imaging feedback into a single platform. This integration can induce multiple synergistic biological responses from a single microwave stimulus, thereby improving overall therapeutic efficiency and stability. Such multifunctional platforms not only broaden the scope of microwave medicine but also provide a material basis for systematic regulation of complex biological processes under pathological conditions.

In this context, a deep understanding and precise control of synergistic sensitization and energy translation mechanisms are particularly critical. Recent studies coupling microwave thermal effects with thermoelectric, pyroelectric, piezoelectric, or magnetic responses have demonstrated unique advantages in amplifying non-thermal biological effects. However, most current research remains at the functional validation stage, with limited quantitative understanding of the contribution ratios, spatiotemporal distribution, and interactions of different translation pathways in biological environments. Future studies should combine in situ characterization techniques with multiscale theoretical models to systematically reveal the intrinsic relationships among material properties, microwave frequency, and irradiation conditions. This approach would enable predictable control of both the intensity and type of biological responses, laying the foundation for the engineering and standardization of microwave medicine.

While the direct effects of microwaves are undoubtedly important, the dynamic evolution of the post-treatment microenvironment is increasingly recognized as a key determinant of long-term therapeutic outcomes. Microwave-induced oxidative stress, structural reorganization, and cellular damage are often accompanied by the release of various endogenous signaling molecules and metabolic byproducts, providing a natural entry point for in situ immune modulation and inflammatory remodeling. By introducing biomaterials that respond to microwave stimulation or changes in the lesion microenvironment, and equipping them with the capacity for molecular capture, enrichment, and controlled release, sustained regulation of immune and inflammatory responses can be achieved during the critical post-treatment phase. Further optimization of the material’s response threshold and release kinetics enables on-demand regulation triggered by microwave or microenvironmental cues, prolonging local action while minimizing systemic side effects, thereby promoting tissue homeostasis and reducing the risk of disease recurrence. This in situ regulation strategy extends microwave therapy from a single intervention to full-course management, demonstrating greater application potential in areas such as oncology. Simultaneously, the development of imaging-guided and integrated therapeutic platforms will further improve the precision and reproducibility of microwave medicine. By endowing microwave-responsive materials with imaging functionality or utilizing signal changes induced under microwave excitation, lesion localization, treatment monitoring, and efficacy assessment can be seamlessly integrated. Imaging feedback not only helps optimize microwave irradiation parameters but also provides critical information for personalized treatment planning. In the future, closed-loop systems combining real-time imaging with microwave modulation are expected to dynamically regulate biological responses, maximizing efficacy while minimizing adverse effects.

Although microwave-responsive biomaterials have shown considerable potential in disease treatment, they still face many practical challenges before they can be clinically translated. Firstly, these material systems are usually complex in structure and often require the cooperation of multiple components such as metals, semiconductors, and organic molecules. It is difficult to ensure the reproducibility and quality controllability of batches during large-scale production. Secondly, the stability, biocompatibility, and long-term safety of the materials in the body have not been fully understood. Especially, their degradation behavior and metabolic pathways still have many unknowns. Moreover, the interaction mechanism between microwave, material, and biology is not yet clear, and there is a lack of quantitative correlation from physical parameters to biological effects, which directly restricts the accuracy of dose control and efficacy prediction. At the same time, the highly heterogeneous tumor or inflammatory microenvironment also makes it difficult to maintain consistent treatment effects. Finally, the relevant regulatory system is not yet complete, standardized evaluation methods are lacking, and the high production cost also slows down the pace of clinical application^[103-105]. Despite the challenges ahead, with the collaborative advancement of material design, biological interface analysis^[106], and regulatory science, microwave-responsive biomaterials are expected to open up a truly controllable, adjustable, and transformable treatment path in the era of precision medicine.

Acknowledgements

The authors used ChatGPT to improve the clarity and readability of the manuscript. All scientific content, interpretations, and conclusions were developed by the authors.

Authors contribution

Song R: Writing-original draft.

Wang S: Conceptualization, resources, visualization, writing-review & editing.

Zhang L, Lu C: Writing-review & editing.

Wang Y, Yuan M: Supervision, writing-review & editing.

Wen L: Funding acquisition, writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

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Availability of data and materials

Not applicable.

Funding

This research was funded by the National Natural Science Foundation of China (Grant No. 82302368), the Guangxi Natural Science Foundation (Grant No. 2025GXNSFAA069529), Guangdong Provincial Applied Science and Technology Research and Development Program (Grant No. 2021B1212040004), Guangdong Province Colleges and Universities Characteristic Innovation Project (Grant No. 2025KTSCX173), and Zhuhai Basic and Applied Basic Research Foundation (Grant No. 2320004002697).

Copyright

© The Author(s) 2026.