Redox-Responsive Polymeric Nanocapsules for Enhanced Tumor-Targeted Delivery of Antimicrobial Peptides

Antimicrobial peptides (AMPs) hold promise as anticancer agents but suffer from proteolytic instability, systemic toxicity, and hemolysis. Here, we report a modular redox-responsive polymeric nanocapsule platform for enhanced tumor-targeted AMP delivery. Using melittin (MEL) as a stringent model, disulfide-crosslinked nanocapsules (nMEL) remain stable and inert under physiological conditions (<5% hemolysis) yet undergo glutathione-triggered shell cleavage in the tumor microenvironment to reactivate lytic activity via controlled MEL liberation. nMEL exhibits ∼4-fold higher tumor accumulation and suppresses subcutaneous tumor growth by ∼80% compared with free MEL. Incorporating phenylboronic acid ligands yields nMEL-PBA, which actively targets hypersalivated tumor cells, achieving 4.5-fold greater pulmonary enrichment and extending median survival to 43 days in a lung metastasis model. This strategy integrates systemic stability, tumor selectivity, and microenvironment-responsive activation, providing a generalizable approach to overcome long-standing barriers in AMP-based cancer therapy.