Enzymatically responsive nanocarriers targeting PD-1 and TGF-β pathways reverse immunotherapeutic resistance and elicit robust therapeutic efficacy

作者：Ying‐Tzu Yen, Zhifan Zhang, Anni Chen, Yuling Qiu, Qin Liu, Qin Wang, Chunhua Li, Chun Wang, Xiaoping Qian, Jie Shao, Fanyan Meng, Lixia Yu, Baorui Liu, Rutian Li · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03129-z · 被引用次数：20 · 研究领域：Nanoplatforms for cancer theranostics、Immune cells in cancer、Nanoparticle-Based Drug Delivery

Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment, yet resistance remains a challenge. Co-inhibition of PD-1/PD-L1 and TGF-β shows promise but faces limited efficacy and systemic toxicity. We developed gelatinase-responsive nanoparticles (GPNPs) delivering anti-PD-1 antibody (αPD-1) and TGF-β receptor I inhibitor galunisertib (Gal). GPNPs effectively inhibit tumor progression without observed side effects. Immune profiling by cytometry assay reveals robust recruitment of both activated and exhausted tumor-infiltrating lymphocytes (TILs) and macrophages. Transcriptomic analysis indicates extracellular matrix modulation, supported by reduced collagen deposition and αSMA expression. Fate mapping demonstrates attenuation of Pdgfrα + fibroblast transition to αSMA myofibroblasts, potentially reversing “immune-exclusive” status. This study validates GPNPs as a promising lung cancer immunotherapy platform, offering mechanistic insights for clinical translation and therapeutic enhancement.