Intracellular Delivery of Full Length Antibodies via Poly-L-lysine-Coated PEG b PLGA Polymersomes Enables Non-invasive Pulmonary Immunotherapy

Abstract

The intracellular delivery of full-length antibodies holds transformative potential for treating a range of diseases but is hindered by poor cellular uptake, extracellular degradation, and limited encapsulation strategies. Here, we report a non-invasive, scalable, and biocompatible nanocarrier system using poly-L-lysine (PLL)-coated PEG-PLGA polymersomes to encapsulate and deliver full-length antibodies intracellularly via passive diffusion. Coating with 30 kDa {varepsilon}-poly-L-lysine enhanced antibody loading efficiency by modulating membrane permeability and reduced vesicle surface charge, facilitating endocytic uptake while preserving antibody activity. The resulting polymersomes exhibited no detectable cytotoxicity and enabled efficient aerosol-based pulmonary delivery to lung epithelial cells in vitro. To our knowledge, this is the first demonstration of using PLL-coated PEG-PLGA polymersomes for passive intracellular delivery of full-length antibodies. This platform opens new avenues for lung-targeted immunotherapy and broadens the translational potential of intracellular antibody therapeutics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/676558v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@e4e1cdorg.highwire.dtl.DTLVardef@a46058org.highwire.dtl.DTLVardef@1b134d0org.highwire.dtl.DTLVardef@1024cc3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPLL coating enhances passive antibody encapsulation efficiency C_LIO_LIPLL-coated polymersomes exhibit tunable, biocompatible surface charge profiles C_LIO_LIEfficient intracellular delivery of full-length antibodies via aerosol-mediated uptake in pulmonary epithelial cells C_LIO_LIFunctional preservation of antibodies post-delivery validates PLL-PEG-PLGA as a protective nanocarrier C_LI