A coordinative modular assembly-constructed self-reinforced nano-therapeutic agent for effective antitumor-immune activation

Immunosuppressive microenvironment and poor immunogenicity are two stumbling blocks in anti-tumor immune activation. Tumor associated macrophages (TAMs) play crucial roles in immunosuppressive microenvironment, while immunogenic cell death (ICD) is a typical strategy to boost immunogenicity. Herein, we developed a coordinative modular assembly-based self-reinforced nanoparticle, (CaO 2 /TA)-(Fe 3+ /BSA) which integrated CaO 2 , Fe 3+ -tannic acid coordinated networks and albumin under the instruction of molecular dynamics simulation. (CaO 2 /TA)-(Fe 3+ /BSA) could significantly enhance Fenton reaction through Fe 3+ self-reduction and H 2 O 2 self-sufficiency, and simultaneously increased intracellular accumulation of Ca 2+ . The self-augmented Fenton reaction with sufficient reactive oxygen species effectively repolarized TAMs and elicited ICD with Ca 2+ overload. Besides, (CaO 2 /TA)-(Fe 3+ /BSA) was confirmed to self-reinforce deep tumor drug delivery by “treatment-delivery” positive feedback based on gp60-mediated transcytosis and M2-like macrophages repolarization-mediated perfusion promotion. Resultantly, (CaO 2 /TA)-(Fe 3+ /BSA) effectively alleviated immunosuppression, provoked local and systemic immune response and potentiated anti-PD-1 antibody therapy. Our strategy highlights a facile and controllable approach to construct penetrated effective antitumor nano-immunotherapeutic agent.