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

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 ε-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 Highlights PLL coating enhances passive antibody encapsulation efficiency PLL-coated polymersomes exhibit tunable, biocompatible surface charge profiles Efficient intracellular delivery of full-length antibodies via aerosol-mediated uptake in pulmonary epithelial cells Functional preservation of antibodies post-delivery validates PLL–PEG–PLGA as a protective nanocarrier