Implantable Bioresponsive Nanoarray Enhances Postsurgical Immunotherapy by Activating Pyroptosis and Remodeling Tumor Microenvironment

Abstract Despite the potential of drug‐loaded scaffolds for tumor recurrence and metastasis (TRM) postoperation, their therapeutic benefits are limited by marked immunosuppressive tumor microenvironment (ITME) and drug‐related untargeted toxicity. Herein, an innovative implantable bioresponsive nanoarray is developed to overcome the above limitations. Chemotherapeutics doxorubicin (DOX) and the epigenetic modulator JQ1 are coloaded into tumor‐targeting nanoparticles (HP‐DOX/JQ1 NPs), which are then linked up through a bio‐responsive linker to construct the nanoarray loading with another part of JQ1 (DOX/JQ1‐IBRN). Under high level of H 2 O 2 in TME, the implanted DOX/JQ1‐IBRN disaggregates and release JQ1 while generating small‐sized HP‐DOX/JQ1 NPs for realizing ITME modulation and tumor‐targeting therapy. JQ1 selectively blocks programmed death‐ligand 1 (PD‐L1) mediated immune evasion and reduces regulatory T cells (Tregs)/‐disruptive effect to facilitate immunopositivity. HP‐DOX/JQ1 NPs destroy residual tumor precisely and trigger gasdermin E (GSDME)‐dependent pyroptosis, further enhancing the number and functions of tumor‐infiltrating T lymphocytes for antitumor immunity. It is demonstrated that DOX/JQ1‐IBRN prevents post‐surgical TRM and prolongs survival in multiple murine tumor models with negligible toxicity. This cooperation in tumor accurate pyroptosis and ITME conversion through the implantable nanoarray (a simple, valid, and safe scaffold) is expected to provide crucial insights for post‐surgical treatment.