Intracellular Delivery of Full-Length Antibodies via Poly-l-lysine-Coated PEG-PLGA Polymersomes Enables Noninvasive Pulmonary Immunotherapy.
The intracellular delivery of full-length antibodies offers substantial therapeutic potential but remains limited by poor cellular uptake, extracellular degradation, and inefficient encapsulation strategies. Here, we report a noninvasive, scalable, and biocompatible nanocarrier platform based on poly-l-lysine (PLL)-coated polyethylene glycol-block-poly(lactic-co-glycolic acid) (PEG-PLGA) polymersomes for efficient intracellular antibody delivery. Coating polymersomes with 30 kDa ε-poly-l-lysine increased antibody encapsulation efficiency to ∼ 80%. It enabled precise modulation of surface charge to a mildly positive ζ-potential (∼+4.5 mV), while maintaining nanoscale dimensions (hydrodynamic diameter ≈ 420 ± 30 nm). The resulting formulation exhibited excellent biocompatibility, preserving >96% cell viability in primary human pulmonary fibroblasts. Importantly, PLL-coated polymersomes facilitated efficient intracellular delivery of full-length antibodies and preserved their biological function, as demonstrated by robust suppression of NOD-like receptor family pyrin domain-containing 3 (NLRP3)-dependent IL-1β signaling. Upon pulmonary administration via aerosolization, polymersomes delivered the antibody efficiently to lung-resident cells in vivo without detectable acute cytotoxicity. To our knowledge, this work represents the first demonstration of PLL-coated PEG-PLGA polymersomes enabling intracellular delivery of full-length antibodies both in vitro and in vivo, establishing a versatile nanoplatform for lung-targeted intracellular antibody therapeutics.