Lu_2026_J.Control.Release_399_115413

The positively charged surface underpins the biointerface activity of cationic liposomes, enabling electrostatic membrane engagement, enhanced cellular internalization, and efficient intracellular delivery. However, its premature exposure during circulation compromises delivery efficiency and increases systemic toxicity risk. Conventional PEGylation improves circulation stability by masking the cationic surface, but persistent shielding suppresses biointerface functions, and repeated dosing may provoke accelerated blood clearance and hypersensitivity reactions. Herein, we developed a physiologically adaptive prodrug liposomal nanoplatform that exploits endogenous carboxylesterase (CES) as a physiological trigger to remove polyethylene glycol (PEG) shielding and restore biointerface functions, including sialic acid-Siglec-E axis-mediated active recognition and cationic lipid-enhanced electrostatic anchoring. This physiologically triggered restoration of biointerface functionality enhanced targeted delivery to myeloid-derived suppressor cells (MDSCs), a key suppressive hub underlying poor immunotherapy responsiveness in cold tumors, while intracellular prodrug activation translated this delivery advantage into pharmacological regulation. The nanoplatform reduced MDSC burden across peripheral and tumor-localized immunity, reactivated systemic antitumor immunity, and attenuated tumor stemness. In Panc02 tumors poorly responsive to immune checkpoint blockade therapy, it markedly potentiated immunotherapy, achieving tumor eradication, durable antitumor immune memory against homologous tumor rechallenge and broader systemic antitumor protection against heterologous tumor challenge. Overall, this work establishes a physiologically adaptive nanotherapeutic strategy that couples programmable biointerface switching with intracellular prodrug activation to potentiate the efficacy and durability of ICB in cold tumors.