Coacervation‐Driven Semipermeable Nanoreactors for Enzymatic Cascade‐Mediated Cancer Combination Therapy with Enhanced Efficacy

Abstract Utilizing enzyme cascades as a promising approach for targeted cancer therapies holds significant potential, yet its clinical effectiveness is substantially hindered by functional losses during delivery. Complex coacervation emerges as an intriguing strategy for designing functional nanoreactors. In this study, a noteworthy achievement is presented in the development of lactobionic acid‐modified tumor microenvironment (TME)‐responsive polyelectrolyte complex vesicles (HGS‐PCVs) based on bioinspired homopolypeptoids, which serve as a facile, intelligent, and highly efficient nanoreactor tunable for glucose oxidase, hemoglobin, and sorafenib (SRF) to hepatic cancer cells. The TME‐responsive permeability of HGS‐PCVs enables the selective entry of glucose into their interior, triggering an enzymatic cascade reaction within the tumor. This intricate process generates toxic hydroxyl radicals while concurrently lowering the pH. Consequently, this pH shift enhances the SRF release, effectively promoting ferroptosis and apoptosis in the target cancer cells. Further, the administration of the HGS‐PCVs not only initiates immunogenic cell death but also plays a crucial role in inducing the maturation of dendritic cells within lymph nodes. It stimulates an adaptive T‐cell response, a crucial mechanism that contributes to impeding the growth of distant tumors in vivo, demonstrating the promising potential of PCVs for cancer immunotherapy.