Remodeling of Effector and Regulatory T Cells by Capture and Utilization of miRNAs Using Nanocomposite Hydrogel for Tumor-Specific Photothermal Immunotherapy

作者：Li Chen, Man Zhu, Handan Zhang, Wenjun Tang, Jie Liu, Xiaoyu Tang, Xiaowei Chang, Zeren Zhu, Tao Liu, Lin Weng, Yanmin Zhang, Xin Chen · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.4c18801 · 被引用次数：15 · 研究领域：Nanoplatforms for cancer theranostics、Immunotherapy and Immune Responses、RNA Interference and Gene Delivery

In immunotherapy for malignant tumors, the dysregulation of the balance between effector T cells and regulatory T cells (Tregs) and the uncertain efficacy due to individual differences have been considered as two critical challenges. In this study, we engineered an injectable nanocomposite hydrogel system (SNAs@M-Gel) capable of suppressing Treg proliferation and blocking PD-1/PD-L1-mediated immune evasion effectively, achieved through the stimulus-responsive modulation of multiple tumor-associated microRNAs. Simultaneously, this system enables microRNA-dependent photothermal immunotherapy, facilitating a highly efficient and personalized approach to tumor treatment. Specifically, oxidized sodium alginate (OSA) and cancer cell membrane (CCM)-encapsulated spherical nucleic acid nanoparticles (SNAs@M) were used to construct the SNAs@M-Gel hydrogel in situ at the tumor site through the formation of pH-sensitive Schiff base bonding and cross-linking using endogenous calcium ions (Ca 2+ ). During treatment, SNAs@M-Gel was retained locally for up to 10 days, and SNAs@M nanoparticles were continuously released into the tumor microenvironment. Through the targeting ability of CCM, SNAs@M precisely entered tumor cells and specifically hybridized with the overexpressed miR-214 and miR-130a, leading to a significant downregulation of PD-L1 expression on tumor cells and the restoration of cytotoxic T lymphocyte (CTL) function suppressed by Tregs, thereby remodeling the immune microenviro...