%0 Journal Article
%T Integration of STING activation and COX-2 inhibition via steric-hindrance effect tuned nanoreactors for cancer chemoimmunotherapy.
%A Zhang P
%A Zhong D
%A Yu Y
%A Wang L
%A Li Y
%A Liang Y
%A Shi Y
%A Duan M
%A Li B
%A Niu H
%A Xu Y
%J Biomaterials
%V 311
%N 0
%D 2024 Dec 29
%M 38954960
%F 15.304
%R 10.1016/j.biomaterials.2024.122695
%X Integrating immunotherapy with nanomaterials-based chemotherapy presents a promising avenue for amplifying antitumor outcomes. Nevertheless, the suppressive tumor immune microenvironment (TIME) and the upregulation of cyclooxygenase-2 (COX-2) induced by chemotherapy can hinder the efficacy of the chemoimmunotherapy. This study presents a TIME-reshaping strategy by developing a steric-hindrance effect tuned zinc-based metal-organic framework (MOF), designated as CZFNPs. This nanoreactor is engineered by in situ loading of the COX-2 inhibitor, C-phycocyanin (CPC), into the framework building blocks, while simultaneously weakening the stability of the MOF. Consequently, CZFNPs achieve rapid pH-responsive release of zinc ions (Zn2+) and CPC upon specific transport to tumor cells overexpressing folate receptors. Accordingly, Zn2+ can induce reactive oxygen species (ROS)-mediated cytotoxicity therapy while synchronize with mitochondrial DNA (mtDNA) release, which stimulates mtDNA/cGAS-STING pathway-mediated innate immunity. The CPC suppresses the chemotherapy-induced overexpression of COX-2, thus cooperatively reprogramming the suppressive TIME and boosting the antitumor immune response. In xenograft tumor models, the CZFNPs system effectively modulates STING and COX-2 expression, converting "cold" tumors into "hot" tumors, thereby resulting in ≈ 4-fold tumor regression relative to ZIF-8 treatment alone. This approach offers a potent strategy for enhancing the efficacy of combined nanomaterial-based chemotherapy and immunotherapy.