Biomimetic self-assembly nanoparticles inhibit serpinB9 and synergistically enhance COD-induced ferroptosis for cancer therapy

Granzyme B (GrB), a crucial serine protease stored in immune cells, plays a pivotal role in combating tumors primarily through GrB-induced apoptosis. However, the elevated expression of SerpinB9 (Sb9), which is a physiological inhibitor of GrB, within tumors acts as an impediment to GrB-induced apoptosis. Protocatechuic acid (PCA), a phenolic acid, has demonstrated promising antitumor potential through ability to inhibit the biological function of Sb9 and enhance the GrB-induced apoptosis. Ferroptosis, an innovative therapeutic strategy for cancer treatment, is also hindered by elevated cholesterol levels within tumors, which suppress ferroptosis and undermine immune function, further reducing GrB secretion. To address these challenges, we engineered multifunctional COD-FePT@PCA NPs@CM (CPM), consisting of metal-phenolic framework nanoparticles loaded with PCA and cholesterol oxidase (COD), which were further encapsulated with macrophage membranes (CM) to construct a biomimetic drug delivery system with enhanced safety and stability. Our findings revealed that CPM exhibited significant antitumor effects both in vitro and in vivo, exhibiting superior stability and optimal biocompatibility. The results revealed that CPM effectively inhibited Sb9 expression and enhanced ferroptosis by downregulating glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), thereby increasing GrB secretion and promoting GrB-induced apoptosis. In vivo studies further confirmed that CPM exhibited potent therapeutic efficacy in tumor-bearing mice and metastasis. Concurrently, the proportion of DC maturation, macrophage polarization, and CTL infiltration was significantly increased, highlighting CPM's ability to elicit robust antitumor immune responses. This study underscores the potential of CPM as a multifunctional therapeutic agent that simultaneously integrates Sb9 inhibition, ferroptosis induction, and immunotherapy, offering a promising strategy for cancer treatment.