A Dual-Targeting Biomimetic Nanozyme Triggering Hypoxia Relief and Macrophage Reprogramming for Synergistic HCC Immunochemotherapy

Abstract

The treatment effectiveness for hepatocellular carcinoma (HCC) is often hindered by an immunosuppressive tumor microenvironment (TME), marked by persistent hypoxia and a high presence of tumor-promoting M2-like tumor-associated macrophages (TAMs). To overcome these barriers, we engineered a dual-targeting biomimetic nanozyme, MnO2@Reg-SPARC (MRS), designed for synergistic immunochemotherapy. This flower-like manganese dioxide nanozyme was functionalized with SPARC antibodies to specifically target both HCC cells and M2-like TAMs, facilitating the delivery of the multikinase inhibitor Regorafenib (Reg). Bioinformatic and experimental validations showed that SPARC-antibody functionalization enhanced nanoparticle accumulation in HCC cells and IL-4-induced M2-like macrophages. The MRS nanosystem exhibited excellent stability and pH/H2O2-responsive drug release. MnO2 functioned as a catalase-mimetic nanozyme, breaking down H2O2 to generate O2, which reduced tumor hypoxia and boosted the immunomodulatory effects of Reg. Reg demonstrated both antitumor and angiogenesis inhibition properties in tumor cells. MRS treatment effectively reprogrammed the immune response by activating the STING/IRF3 signaling pathway, facilitating the shift of macrophages from a pro-tumor M2-like phenotype to an antitumor M1-like phenotype. In vivo studies further revealed that MRS achieved prolonged blood circulation and superior tumor accumulation, resulting in robust tumor growth inhibition with negligible systemic toxicity. This biomimetic platform provides a dual-targeting approach that combines hypoxia relief, targeted chemotherapy, and innate immune reprogramming to precisely treat hepatocellular carcinoma.