pH-responsive polymeric nanoparticles for peptide delivery: Synergistic STING pathway activation enhances tumor immunotherapy

作者：Mengjie Rui, Haidan Tang, Lianglai Gao, Yufeng Hu, Wenyan Liang, Yinfeng Li, Chunlai Feng · 发表于：International Journal of Pharmaceutics X · 年份：2025 · DOI：10.1016/j.ijpx.2025.100412 · 被引用次数：3 · 研究领域：interferon and immune responses、Peptidase Inhibition and Analysis、Nanoplatforms for cancer theranostics

Peptides hold great promise in tumor immunotherapy, but suffer from poor stability and short systemic circulation. To overcome these challenges, we developed a pH-responsive nanodelivery systems (P-NPs) based on the amphiphilic block polymer PEO-PC7A. In addition to its role in peptide encapsulation and protection, PEO-PC7A intrinsically acted as a stimulator of the interferon genes (STING) agonist, activating the cGAS-STING signaling pathway and remodeling the immunosuppressive tumor microenvironment. P-NPs were successfully prepared via a self-assembly technique, yielding nanoparticles with a uniform diameter of 91.2 ± 3.5 nm. Their pH-responsive behavior was confirmed by significant change in particle size and accelerated peptide release under acidic conditions. In vitro , P-NPs effectively increased the cytotoxic activity of T cells and induced higher interleukin-2 (IL-2) secretion compared to free peptide. In a 4 T1 tumor-bearing mouse model, intravenous administration of P-NPs achieved greater tumor growth inhibition and higher intratumoral interferon-γ (IFN-γ) levels than free peptide, with minimal systemic toxicity and no significant impact on body weight. Overall, our study presented a novel multifunctional peptide nanocarrier that enhanced tumor immunotherapy efficacy by concurrently improving peptide delivery and stimulating innate immunity, providing a promising foundation for the further development of innovative combination cancer immunotherapy strategies. • A p...