A Biomimetic Nanomedicine for Remodeling the Immune Microenvironment to Potentiating Anti-Tumor Therapy.

Abstract

Systemic therapeutic modalities that possess the capability to activate immune response represent efficacious strategy for managing advanced hepatocellular carcinoma (HCC). Nonetheless, the therapeutic efficacy is substantially constrained by the tumor immunosuppressive microenvironment (TIME) engendered by hypoxia and lactate accumulation in the tumor region. Here, an efficient therapeutic strategy based on a biomimetic nanomedicine is established to remodel TIME and stimulate immune activation for HCC treatment. First, Glucose oxidase (GOx)-MnO₂ self-assembled particles (GM) are synthesized by a facile biomineralization process and further loaded with NO donor (L-Arginine, L-Arg) (GMA). Next, the biomimetic nanomedicine is constructed by co-loading GMA and β-lapachone (β-lap, a drug for DNA damage) into nanoliposomes (GMA-LP), which is found to regulate glucose metabolism to reduce lactate production and concurrently generate oxygen (O₂) to alleviate tumor hypoxia, thus mitigating tumor immunosuppression. More importantly, β-Lap released from GMA-LP NPs can induce DNA damage in tumor cells, while NO generated by H₂O₂-mediated L-Arginine activation further obstructs the self-repair of damaged DNA, thereby ultimately leading to the in situ activation of STING pathway for eliciting antitumor immune response. Overall, this study provides a universally new strategy for an effective treatment toward advanced HCC, presenting great clinical research values and scientific significance.