Hao Xinyan, Tang Yucheng, Xu Wenjie, Wang Ming, Liu Jiayi, Li Yongjiang, He Jun, Peng Yanjin, Sun Pengcheng, Liao Dehua, Hu Xiongbin, Tang Tiantian, Zhou Min, Han Ruyue, Wang Jiemin, Conde João, Xiang Daxiong, Wu Junyong
Department of Pharmacy The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Institute of Clinical Pharmacy, Central South University, Changsha, 410011, China.
J Nanobiotechnology. 2025 Jan 15;23(1):14. doi: 10.1186/s12951-025-03091-w.
Glioblastoma multiforme (GBM) is characterized by pronounced immune escape and resistance to chemotherapy-induced apoptosis. Preliminary investigations revealed a marked overexpression of gasdermin E (GSDME) in GBM. Notably, cisplatin (CDDP) demonstrated a capacity of inducing pyroptosis by activating caspase-3 to cleave GSDME, coupled with the release of proinflammatory factors, indicating the potential as a viable approach of inducing anti-tumor immune activation. For the effective delivery of CDDP, the CDDP-polyphenol nanocomplexes were prepared, and catalase and copper ions were incorporated to fortify structural integrity, enhance glutathione (GSH) responsiveness, and ameliorate tumor hypoxia. Additionally, BV2 microglial cells were engineered to overexpress programmed death-1 (PD-1), and the membrane is employed for nanocomplex coating, effectively blocking the CDDP-induced upregulation of programmed death ligand 1 (PD-L1). Furthermore, the angiopep-2 peptide was modified to efficiently cross the blood brain barrier and specifically target GBM cells. In vitro analyses confirmed potent cytotoxicity and characteristic induction of pyroptosis. In vivo assays corroborated the enhancement of tumor targeting, culminating in an obvious suppression of tumor proliferation. A notable activation of immune cells was observed within tumors and lymph nodes, indicative of a synergistic effect of chemotherapy and immunotherapy, underscoring its potential as a safe and efficacious therapeutic strategy against GBM.
多形性胶质母细胞瘤（GBM）的特征是明显的免疫逃逸和对化疗诱导的细胞凋亡具有抗性。初步研究显示，GBM中gasdermin E（GSDME）明显过表达。值得注意的是，顺铂（CDDP）通过激活半胱天冬酶-3裂解GSDME，表现出诱导细胞焦亡的能力，同时释放促炎因子，这表明其具有诱导抗肿瘤免疫激活的潜在可行性。为了有效递送CDDP，制备了CDDP-多酚纳米复合物，并加入过氧化氢酶和铜离子以加强结构完整性、增强谷胱甘肽（GSH）反应性并改善肿瘤缺氧状况。此外，对BV2小胶质细胞进行基因工程改造使其过表达程序性死亡蛋白1（PD-1），并将该细胞膜用于纳米复合物包被，有效阻断CDDP诱导的程序性死亡配体1（PD-L1）上调。此外，对血管活性肠肽-2（angiopep-2）肽进行修饰，以有效穿过血脑屏障并特异性靶向GBM细胞。体外分析证实了其强大的细胞毒性和对细胞焦亡的特征性诱导作用。体内试验证实肿瘤靶向性增强，最终明显抑制肿瘤增殖。在肿瘤和淋巴结内观察到免疫细胞显著激活，表明化疗和免疫疗法具有协同效应，凸显了其作为一种安全有效的GBM治疗策略的潜力。
