Journal of nanobiotechnology · 2026
A neutrophil-tumor cascade-targeting Trojan horse for heterobifunctional prodrug delivery to enhance cGAS-STING cancer immunotherapy.
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Zhang Huamiao, Li Yang, Bi Qiuchen, Zhu Heping, Wang Huiwen, Wang Zhao, Ma Zhangqiang, Liu Huiping, Zhu Xiaoling, Cao Jiaqi, Wang Xin, Tang Zhe, Chen Xiaoyuan, Tang Longguang, Peng Kesong
Аннотация
BACKGROUND: Since the discovery of the cGAS-STING pathway, attempts to utilize it as an anti-tumor immunotherapy have attracted significant research interest and investment. However, relevant clinical translation remains hindered by immune evasion and systemic toxicity.
RESULTS: We introduce BMSA, a first-in-class STING-PD-L1 heterobifunctional prodrug in which the PD-L1 inhibitor BMS-1 and the STING agonist MSA-2 are bridged by a tumor-cleavable linker. BMSA executes glutathione-triggered extracellular release of BMS-1 and intracellular esterase-mediated liberation of MSA-2, synchronizing dual immune signals at their respective sites of action. To confine activation to the tumor, we encapsulated BMSA into neutrophil-hitchhiking nanoparticles (T-NPs). After tail intravenous injection, T-NPs hijacked circulating neutrophils, accumulated at irradiated tumors via X-ray-induced inflammation, and exposed the fibrin-binding peptide CREKA through MMP-2/9 cleavage, producing markedly intratumoral accumulation while minimizing systemic exposure.
CONCLUSION: This "Neutrophil-Tumor" cascade delivered heterobifunctional immunomodulation drugs with spatial and temporal precision, offering a translatable solution to the toxicity-efficacy dilemma that currently constrains STING-based cancer therapy.
RESULTS: We introduce BMSA, a first-in-class STING-PD-L1 heterobifunctional prodrug in which the PD-L1 inhibitor BMS-1 and the STING agonist MSA-2 are bridged by a tumor-cleavable linker. BMSA executes glutathione-triggered extracellular release of BMS-1 and intracellular esterase-mediated liberation of MSA-2, synchronizing dual immune signals at their respective sites of action. To confine activation to the tumor, we encapsulated BMSA into neutrophil-hitchhiking nanoparticles (T-NPs). After tail intravenous injection, T-NPs hijacked circulating neutrophils, accumulated at irradiated tumors via X-ray-induced inflammation, and exposed the fibrin-binding peptide CREKA through MMP-2/9 cleavage, producing markedly intratumoral accumulation while minimizing systemic exposure.
CONCLUSION: This "Neutrophil-Tumor" cascade delivered heterobifunctional immunomodulation drugs with spatial and temporal precision, offering a translatable solution to the toxicity-efficacy dilemma that currently constrains STING-based cancer therapy.