Biodegradable polymersomes encapsulating copper peroxide and gemcitabine for targeted chemoimmunotherapy

Herein, we engineered biodegradable, ROS-responsive polymersomes (HA-PGC) encapsulating gemcitabine (GEM) and copper peroxide nanoparticles (CuO₂), functionalized with hyaluronic acid (HA) to target CD44-overexpressing TNBC cells. Upon reaching the acidic TME, CuO₂ decomposes to generate hydrogen peroxide (H₂O₂) and Cu 2+ ions, triggering robust ROS production via a Cu-based Fenton-like reaction. Elevated ROS simultaneously suppresses cytidine deaminase (CDA), enhancing GEM activation, and depletes glutathione (GSH), reducing ROS scavenging. The induced oxidative stress further promotes immunogenic cell death (ICD), facilitating dendritic cell maturation and enhancing tumor-infiltrating lymphocytes. Consequently, HA-PGC nanoparticles effectively convert cold tumors into hot tumors, significantly improving anti-PD-L1 immunotherapy efficacy. We demonstrated a novel, multifunctional nanoparticle platform combining chemodynamic therapy and immunotherapy, presenting a promising strategy to overcome resistance in triple-negative breast cancer treatment and guide future intelligent immunotherapeutic system design. • Biodegradable polymersomes (HA-PGC) co-encapsulating gemcitabine (GEM) and copper peroxide (CuO₂) nanoparticles was developed. • HA-PGC was functionalized with hyaluronic acid (HA) for active tumor targeting. • The polymersomes disassemble, releasing GEM and CuO₂ under acidic tumor environment. • HA-PGC effectively suppresses tumor growth in 4 T1-bearing mice and converts immunologically “cold” tumors into “hot” tumors. • This tumor responsive nanoplatform integrates chemodynamic therapy with immunotherapy.