Engineering immune cells with membrane-fusogenic liposomes: A new frontier in adoptive cell therapy

Engineering immune cells with membrane-fusogenic liposomes: A new frontier in adoptive cell therapy

Qingguo Zhong
1
,
Yuxin Huang
2,3
,
Zhenhua Li
4
,
Chunxiong Zheng
5,*
,
Yu Tao
2,6
,
Mingqiang Li
2,6,7,*
*Correspondence to: Chunxiong Zheng, School of Chemistry, South China Normal University, Guangzhou 510006, Guangdong, China. E-mail: zhengchunxiong@m.scnu.edu.cn
Mingqiang Li, Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, Guangdong, China; Cell-Gene Therapy Center, Institute for Frontier Interdisciplinary Research in Health Sciences and Technology, Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Key Laboratory for Polymeric Composite and Functional Materials of the Ministry of Education, Sun Yat-sen University, Guangzhou 510275, Guangdong, China. E-mail: limq567@mail.sysu.edu.cn
BME Horiz. 2027;5:202625. 10.70401/bmeh.2026.0035
Received: June 16, 2026Accepted: September 07, 2026Published: September 07, 2026
Tips Icon
This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Adoptive cell therapy continues to encounter diverse hurdles in treating solid tumors, including poor infiltration, an immunosuppressive microenvironment, and tumor immune evasion, necessitating the endowment of effector cells with multiple functionalities. However, conventional cell-engineering techniques, including genetic editing and chemical modification, merely modulate a single functional axis to yield a monofunctional effector cell that can overcome only one physiological barrier, leading to insufficient solid tumor suppression. Recently, membrane-fusogenic liposomes have emerged as a multiplex engineering tool capable of straightforwardly producing multifunctional effector cells to synchronously surmount multiple challenges for effective antitumor efficacy. Through a fusion process, this liposome concurrently achieves immune cell surface functionalization and intracellular delivery of bioactive molecules, thereby endowing effector cells with multiple functionalities within a single step. This minireview summarizes recent advances in the use of fusogenic liposomes for immune cell engineering to boost their therapeutic efficiency on solid tumors. We discuss their design principles, representative applications, and analyze their technical advantages and current limitations. Looking forward, we propose that membrane-fusogenic liposomes hold potential to advance the development of multimodal engineered immune cells for next-generation cancer immunotherapies.

Keywords

Adoptive cell therapy, cell engineering, membrane fusion, liposome

References

  • 1. Finck AV, Blanchard T, Roselle CP, Golinelli G, June CH. Engineered cellular immunotherapies in cancer and beyond. Nat Med. 2022;28(4):678-689.
    [DOI]
  • 2. Kalbasi A, Siurala M, Su LL, Tariveranmoshabad M, Picton LK, Ravikumar P, et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature. 2022;607(7918):360-365.
    [DOI] [PubMed] [PMC]
  • 3. Eckman N, Nejatfard A, Cavet R, Grosskopf AK, Appel EA. Biomaterials to enhance adoptive cell therapy. Nat Rev Bioeng. 2024;2(5):408-424.
    [DOI]
  • 4. Zheng C, Zhang J, Chan HF, Hu H, Lv S, Na N, et al. Engineering nano-therapeutics to boost adoptive cell therapy for cancer treatment. Small Methods. 2021;5(5):e2001191.
    [DOI] [PubMed]
  • 5. Flugel CL, Majzner RG, Krenciute G, Dotti G, Riddell SR, Wagner DL, et al. Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nat Rev Clin Oncol. 2023;20(1):49-62.
    [DOI] [PubMed] [PMC]
  • 6. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: What we know so far. Nat Rev Clin Oncol. 2023;20(6):359-371.
    [DOI]
  • 7. Dagher OK, Posey AD Jr. Forks in the road for CAR T and CAR NK cell cancer therapies. Nat Immunol. 2023;24(12):1994-2007.
    [DOI]
  • 8. Lee A. Obecabtagene autoleucel: First approval. Mol Diagn Ther. 2025;29(3):419-423.
    [DOI]
  • 9. Laskowski TJ, Biederstädt A, Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer. 2022;22(10):557-575.
    [DOI]
  • 10. Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947-953.
    [DOI]
  • 11. Albelda SM. CAR T cell therapy for patients with solid tumours: Key lessons to learn and unlearn. Nat Rev Clin Oncol. 2024;21(1):47-66.
    [DOI]
  • 12. Xu F, Ni Q, Gong N, Xia B, Zhang J, Guo W, et al. Delivery systems developed for treatment combinations to improve adoptive cell therapy. Adv Mater. 2024;36(40):e2407525.
    [DOI] [PubMed]
  • 13. Liang J, Fang Y, Wu B, Kong N, Li S, Cheng J, et al. Harnessing self-assembling peptides on γδ T cells to enhance anti-tumor immunity. Polym Sci Technol. 2026;2(5):295-305.
    [DOI]
  • 14. Baulu E, Gardet C, Chuvin N, Depil S. TCR-engineered T cell therapy in solid tumors: State of the art and perspectives. Sci Adv. 2023;9(7):eadf3700.
    [DOI]
  • 15. Hou AJ, Chen LC, Chen YY. Navigating CAR-T cells through the solid-tumour microenvironment. Nat Rev Drug Discov. 2021;20(7):531-550.
    [DOI]
  • 16. Wang Y, Li Z, Mo F, Chen-Mayfield TJ, Saini A, LaMere AM, et al. Chemically engineering cells for precision medicine. Chem Soc Rev. 2023;52(3):1068-1102.
    [DOI] [PubMed]
  • 17. Jadlowsky JK, Hexner EO, Marshall A, Grupp SA, Frey NV, Riley JL, et al. Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies. Nat Med. 2025;31(4):1134-1144.
    [DOI] [PubMed]
  • 18. Zhang AQ, Hostetler A, Chen LE, Mukkamala V, Abraham W, Padilla LT, et al. Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR. Nat Biomed Eng. 2023;7(9):1113-1128.
    [DOI] [PubMed] [PMC]
  • 19. Xue Y, Che J, Ji X, Li Y, Xie J, Chen X. Recent advances in biomaterial-boosted adoptive cell therapy. Chem Soc Rev. 2022;51(5):1766-1794.
    [DOI] [PubMed]
  • 20. Zheng C, Tao Y, Lao YH, Xie X, Li M. Fusogenic polymer-liposome-hybrid nanoparticle: A versatile platform for synchronized drug delivery to the cytoplasm and cell membrane. Polym Sci Technol. 2026;2(2):62-65.
    [DOI]
  • 21. Xu Y, Chen J, Ding J, Sun J, Song W, Tang Z, et al. Synthetic polymers for drug, gene, and vaccine delivery. Polym Sci Technol. 2025;1(3):171-220.
    [DOI]
  • 22. Choi BD, Yu X, Castano AP, Bouffard AA, Schmidts A, Larson RC, et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat Biotechnol. 2019;37(9):1049-1058.
    [DOI] [PubMed]
  • 23. Simon B, Harrer DC, Schuler-Thurner B, Schaft N, Schuler G, Dörrie J, et al. The siRNA-mediated downregulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-T-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma. Exp Dermatol. 2018;27(7):769-778.
    [DOI] [PubMed]
  • 24. Kong H, Yi K, Zheng C, Lao YH, Zhou H, Chan HF, et al. Membrane-fusogenic biomimetic particles: A new bioengineering tool learned from nature. J Mater Chem B. 2022;10(36):6841-6858.
    [DOI] [PubMed]
  • 25. Zhong Q, Zheng C, Yi K, Mintz RL, Lv S, Tao Y, et al. Structural and componential design: New strategies regulating the behavior of lipid-based nanoparticles in vivo. Biomater Sci. 2023;11(14):4774-4788.
    [DOI] [PubMed]
  • 26. Zheng C, Zhong Q, Yi K, Kong H, Cao F, Zhuo C, et al. Anti-phagocytosis-blocking repolarization-resistant membrane-fusogenic liposome (ARMFUL) for adoptive cell immunotherapy. Sci Adv. 2023;9(32):eadh2413.
    [DOI] [PubMed] [PMC]
  • 27. Zheng C, Liu Z, Yi K, Zhong Q, Kong H, Qiu D, et al. Fusogenic liposome-engineered natural killer cells for solid tumor therapy. Cell Biomater. 2026.
    [DOI]
  • 28. Zheng C, Yi K, Du Y, Zhong Q, Kong H, Wang H, et al. Immuno-packed T-cell-fusogenic liposome empowers adoptive T cell therapy for solid tumor treatment. Adv Mater. 2026;38(8):e10842.
    [DOI] [PubMed]
  • 29. Zheng C, Zhong Q, Song W, Yi K, Kong H, Wang H, et al. Membrane-fusion-mediated multiplex engineering of tumor cell surface glycans for enhanced NK cell therapy. Adv Mater. 2023;35(14):e2206989.
    [DOI] [PubMed]
  • 30. Kong H, Zheng C, Yi K, Mintz RL, Lao YH, Tao Y, et al. An antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo. Nat Commun. 2024;15(1):4267.
    [DOI] [PubMed] [PMC]
  • 31. Yi K, Kong H, Zheng C, Zhuo C, Jin Y, Zhong Q, et al. A LIGHTFUL nanomedicine overcomes EGFR-mediated drug resistance for enhanced tyrosine-kinase-inhibitor-based hepatocellular carcinoma therapy. Biomaterials. 2023;302:122349.
    [DOI] [PubMed]
  • 32. Zhao Y, Hou X, Wang Z, Peng S, Zheng C, Huang Q, et al. A mechanical immune checkpoint inhibitor stiffens tumor cells to potentiate antitumor immunity. Angew Chem Int Ed. 2025;64(5):e202417518.
    [DOI]
  • 33. Kong H, Zhuo C, Yi K, Zheng C, Mintz RL, Lao YH, et al. Hepatocyte-confined CRISPR/Cas9-based nanocleaver precisely eliminates viral DNA for efficient and safe treatment of hepatitis B virus infection. Nano Today. 2023;53:102040.
    [DOI]
  • 34. Zhao Y, Qin J, Yu D, Liu Y, Song D, Tian K, et al. Polymer-locking fusogenic liposomes for glioblastoma-targeted siRNA delivery and CRISPR-Cas gene editing. Nat Nanotechnol. 2024;19(12):1869-1879.
    [DOI] [PubMed]
  • 35. Ren X, Xue R, Luo Y, Wang S, Ge X, Yao X, et al. Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies. Nat Commun. 2024;15(1):5035.
    [DOI] [PubMed] [PMC]
  • 36. Zhao Z, Yang Y, Sheng T, Bao Y, Yu R, Yu X, et al. Platelet-drug conjugates engineered via one-step fusion approach for metastatic and postoperative cancer treatment. Angew Chem Int Ed. 2024;63(37):e202403541.
    [DOI] [PubMed]
  • 37. Wang X, Sun X, Zeng Y, Liu S, Yi Q, Wu Y. Membrane fusion strategy boosts immune homeostasis, mobilizing macrophages to eliminate bacteria and accelerate skin regeneration in infected burn wound. Adv Funct Mater. 2025;35(10):2416791.
    [DOI]
  • 38. Yang X, Bian J, Wang Z, He M, Yang Y, Li Q, et al. A bio-liposome activating natural killer cell by illuminating tumor homogenization antigen properties. Adv Sci. 2023;10(12):e2205449.
    [DOI] [PubMed] [PMC]
  • 39. Zhao X, Liu Q, Zheng C, Wang Y, Zhao Y, Zhang Z, et al. Tumor cell surface modification with immuno-amplified nanoparticles to enhance cancer immunotherapy. Mater Today Chem. 2023;27:101303.
    [DOI]
  • 40. Du Y, Kong H, Zheng H, Lin X, Lu T, Zhao Y, et al. Reactive-oxygen-species-unlocking fusogenic liposome for spatially-selectively cytoplasmic antioxidant delivery and synergistic acute liver injury treatment. Chem Eng J. 2026;537:176132.
    [DOI]
  • 41. Chen Z, Yang Z, Wang C, Liu X, Fiaz J, Wang W, et al. Stiffness-gated cytoplasmic mRNA delivery through engineered membrane fusion for breast cancer immunotherapy. Adv Mater. 2026;38(12):e18208.
    [DOI] [PubMed]
  • 42. Zheng H, Zheng C, Du Y, Lin X, Zhao Y, Wang K, et al. Lipid modified with pyridinium betaine manipulates liposomal membrane fusion behavior for spatially confined cytoplasmic delivery. Angew Chem Int Ed. 2026;65(21):e22025.
    [DOI] [PubMed]
  • 43. Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell. 2016;167(2):419-432.e16.
    [DOI] [PubMed] [PMC]
  • 44. Rurik JG, Tombácz I, Yadegari A, Méndez Fernández PO, Shewale SV, Li L, et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022;375(6576):91-96.
    [DOI] [PubMed] [PMC]

© The Author(s) 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Publisher’s Note

Science Exploration remains a neutral stance on jurisdictional claims in published maps and institutional affiliations. The views expressed in this article are solely those of the author(s) and do not reflect the opinions of the Editors or the publisher.

Share And Cite

Science Exploration Style
Zhong Q, Huang Y, Li Z, Zheng C, Tao Y, Li M. Engineering immune cells with membrane-fusogenic liposomes: A new frontier in adoptive cell therapy. BME Horiz. 2027;5:202625. https://doi.org/10.70401/bmeh.2026.0035

Submit a Manuscript
Author Instructions
Cite this Article
Export Citation
Article Metrics
0
View
0
Download
Cited
Article Updates
Citation Icon Get citation