An Iron‐Polyphenol Decorated siRNA‐Encapsulated Nanomedicine Multifacetedly Promoted Macrophage Phagocytosis for Synergistic Ferroptosis‐Immunotherapy

Abstract Macrophages are vital components of the innate immune system, capable of directly engulfing tumor cells. However, tumor cells can cunningly evade recognition and phagocytosis by macrophages. In light of this, an iron‐polyphenol‐decorated poly(ethylene glycol)‐poly(lactic‐co‐glycolic acid (PEG‐PLGA) nanoparticle has been developed with efficient siRNA encapsulation (NP siCD47 @Fe‐TA) to trigger the ferroptosis in tumor cell and also elicit the macrophage‐mediated immunotherapy. The Fe‐TA (Tannic acid) shell of NP siCD47 @Fe‐TA induces the ferroptosis in tumor cell, which consequently produces oxygenated phosphatidylethanolamine 1‐steaoryl‐2‐15‐HpETE‐sn‐glycero‐3‐phosphatidylethanolamine (SAPE‐OOH) in the cell membrane and achieve the surface exposure of calreticulin (CRT). Meanwhile, the encapsulated siCD47 of NP siCD47 @Fe‐TA efficiently down‐regulates the CD47 receptor in the tumor cell membrane. The exposure of SAPE‐OOH and CRT in the cell membrane and down‐regulation of CD47 receptor remarkably promoted the phagocytosis of tumor cells by macrophage and elicited the systemic anticancer immune response. Eventually, the NP siCD47 @Fe‐TA can efficiently suppress the tumor growth. Moreover, after combination with immune checkpoint blockade (ICB) antibody, NP siCD47 @Fe‐TA remarkably inhibits tumor progress and metastasis in the cold triple‐negative 4T1 breast cancer model.