Enhancing Transduction and Immune Resilience in Viral Gene Therapy Through Erythrocyte-Derived Membrane Encapsulation

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Abstract
Viral vectors such as adenovirus (Ad) and lentivirus (LV) are central to gene therapy owing to their transduction efficiency and broad applicability; however, their clinical translation is often limited by immunogenicity, rapid clearance, and reduced bioavailability. Non-enveloped Ad vectors are highly susceptible to neutralization by pre-existing antibodies, while enveloped LVs remain vulnerable to immune surveillance and off-target clearance. In this study, a biomimetic encapsulation strategy using erythrocyte-derived membranes (EDMs) is reported to enhance viral immune resilience and functional gene delivery. Ad-GFP and LV-mCherry were successfully encapsulated within EDM using an extrusion-based assembly approach, resulting in uniform membrane-coated particles with physicochemical properties characteristic of erythrocyte membranes. EDM encapsulation significantly enhanced in vitro transduction efficiency of both viral platforms across multiple cancer cell lines without compromising viral activity. Notably, EDM-Ad-GFP demonstrated robust protection against neutralizing antibodies, achieving significantly higher transduction of HEK293 cells in the presence of diluted human serum compared to unencapsulated Ad. These findings indicate that EDM encapsulation can effectively shield viral vectors from immune recognition while improving cellular uptake and transduction performance. Collectively, this work establishes EDM encapsulation as a versatile and scalable platform to enhance the efficacy, durability, and translational potential of viral gene delivery systems.
Funding Information
  • University of California (13991)

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