Tumor-Acidity and Bioorthogonal Chemistry-Mediated On-Site Size Transformation Clustered Nanosystem to Overcome Hypoxic Resistance and Enhance Chemoimmunotherapy

作者：Kewei Wang, Maolin Jiang, Jielian Zhou, Ye Liu, Qingyu Zong, Youyong Yuan · 发表于：ACS Nano · 年份：2022 · DOI：10.1021/acsnano.1c08232 · 被引用次数：82 · 研究领域：Cancer, Hypoxia, and Metabolism、Nanoplatforms for cancer theranostics、Cancer Research and Treatments

Hypoxia, a common feature of most solid tumors, causes severe tumor resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem is designed to overcome hypoxic resistance and enhance chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive group poly(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry to form large-sized aggregates in tumor tissue to enhance accumulation and retention. Subsequently, another tumor-acidity responsive group of the maleic acid amide with a slow response rate was cleaved allowing the aggregates to slowly dissociate into ultrasmall nanoparticles with better tumor penetration ability for the delivery of doxorubicin (DOX) and nitric oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced DOX resistance and boost the antitumor immune response through a reprogrammed tumor immune microenvironment. This tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem not only helps to counteract a hypoxia-induced chemoresistance and enhance antitumor immune responses but also provides a general drug delivery strategy for enhanced tumor accumulation and penetration.