Han Ruyue, Sun Pengcheng, Zhou Min, Xu Wenjie, Hao Xinyan, Peng Yanjin, Tang Yucheng, Liu Xinying, Huang Hai, Guo Mengen, Tang Tiantian, Hu Xiongbin, Xiang Daxiong, Wu Junyong
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, 410011, China.
Mater Today Bio. 2025 Jun 13;33:101982. doi: 10.1016/j.mtbio.2025.101982. eCollection 2025 Aug.
Granzyme B (GrB), a crucial serine protease stored in immune cells, plays a pivotal role in combating tumors primarily through GrB-induced apoptosis. However, the elevated expression of SerpinB9 (Sb9), which is a physiological inhibitor of GrB, within tumors acts as an impediment to GrB-induced apoptosis. Protocatechuic acid (PCA), a phenolic acid, has demonstrated promising antitumor potential through ability to inhibit the biological function of Sb9 and enhance the GrB-induced apoptosis. Ferroptosis, an innovative therapeutic strategy for cancer treatment, is also hindered by elevated cholesterol levels within tumors, which suppress ferroptosis and undermine immune function, further reducing GrB secretion. To address these challenges, we engineered multifunctional COD-FePT@PCA NPs@CM (CPM), consisting of metal-phenolic framework nanoparticles loaded with PCA and cholesterol oxidase (COD), which were further encapsulated with macrophage membranes (CM) to construct a biomimetic drug delivery system with enhanced safety and stability. Our findings revealed that CPM exhibited significant antitumor effects both in vitro and in vivo, exhibiting superior stability and optimal biocompatibility. The results revealed that CPM effectively inhibited Sb9 expression and enhanced ferroptosis by downregulating glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), thereby increasing GrB secretion and promoting GrB-induced apoptosis. In vivo studies further confirmed that CPM exhibited potent therapeutic efficacy in tumor-bearing mice and metastasis. Concurrently, the proportion of DC maturation, macrophage polarization, and CTL infiltration was significantly increased, highlighting CPM's ability to elicit robust antitumor immune responses. This study underscores the potential of CPM as a multifunctional therapeutic agent that simultaneously integrates Sb9 inhibition, ferroptosis induction, and immunotherapy, offering a promising strategy for cancer treatment.
颗粒酶B（GrB）是一种储存在免疫细胞中的关键丝氨酸蛋白酶，主要通过GrB诱导的细胞凋亡在对抗肿瘤中发挥关键作用。然而，丝氨酸蛋白酶抑制剂B9（Sb9）作为GrB的生理抑制剂，在肿瘤内表达升高，阻碍了GrB诱导的细胞凋亡。原儿茶酸（PCA）是一种酚酸，通过抑制Sb9的生物学功能和增强GrB诱导的细胞凋亡，显示出有前景的抗肿瘤潜力。铁死亡是一种创新的癌症治疗策略，肿瘤内升高的胆固醇水平也会阻碍它，胆固醇会抑制铁死亡并破坏免疫功能，进而减少GrB的分泌。为应对这些挑战，我们构建了多功能COD-FePT@PCA NPs@CM（CPM），它由负载PCA和胆固醇氧化酶（COD）的金属酚框架纳米颗粒组成，这些纳米颗粒进一步用巨噬细胞膜（CM）包裹，以构建一种具有更高安全性和稳定性的仿生药物递送系统。我们的研究结果表明，CPM在体外和体内均表现出显著的抗肿瘤作用，具有卓越的稳定性和最佳的生物相容性。结果显示，CPM通过下调谷胱甘肽过氧化物酶4（GPX4）和铁死亡抑制蛋白1（FSP1）有效抑制Sb9表达并增强铁死亡，从而增加GrB分泌并促进GrB诱导的细胞凋亡。体内研究进一步证实，CPM在荷瘤小鼠中表现出强大的治疗效果并能抑制转移。同时，树突状细胞成熟、巨噬细胞极化和细胞毒性T淋巴细胞浸润的比例显著增加，突出了CPM引发强大抗肿瘤免疫反应的能力。这项研究强调了CPM作为一种多功能治疗剂的潜力，它同时整合了Sb9抑制、铁死亡诱导和免疫治疗，为癌症治疗提供了一种有前景的策略。
