Zhai Yihui, Zhang Wen, Wang Jinming, Kong Ying, Rong Rong, Lang Tianqun, Zheng Chao, Wang Yanke, Yu Yang, Zhu Helen He, Cai Ying, Zhang Pengcheng, Li Yaping
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Adv Sci (Weinh). 2025 Jan;12(4):e2409194. doi: 10.1002/advs.202409194. Epub 2024 Dec 3.
Interleukin 15 (IL15) is crucial for fostering the survival and proliferation of nature killer (NK) cells and cytotoxic T lymphocytes (CTLs), playing a pivotal role in tumor control. However, IL15 supplementary therapy encounters challenges such as systemic inflammation and non-specific stimulation of cancer cells. Herein, a nanovesicle termed DoxFILN, comprising a membrane presenting IL15/IL15 receptor α complexes (IL15c) and a core of doxorubicin-loaded ferritin (Dox-Fn) are reported. The DoxFILN significantly enhances the densities and activities of intratumoral CTLs and NK cells. Mechanistically, DoxFILN undergoes deshelling in the acidic tumor microenvironment, releasing Dox-Fn and membrane-bound IL15c. Dox-Fn selectively target transferrin receptors on cancerous cells, facilitating intracellular Dox release and inducing immunogenic cell death. Concurrently, membrane-bound IL15c recognizes and activates IL15 receptor β/γc heterodimers, leading to a remarkable increase in the proliferation and activation of CTLs (16-fold and 28-fold) and NK cells (37-fold and 50-fold). The IL15-displaying nanovesicle introduced here holds promise as a potential platform for immunochemotherapy in the treatment of cancer.
白细胞介素15（IL15）对于促进自然杀伤（NK）细胞和细胞毒性T淋巴细胞（CTL）的存活和增殖至关重要，在肿瘤控制中发挥着关键作用。然而，IL15补充疗法面临诸如全身炎症和癌细胞的非特异性刺激等挑战。在此，报道了一种名为DoxFILN的纳米囊泡，其由呈现IL15/IL15受体α复合物（IL15c）的膜和负载阿霉素的铁蛋白（Dox-Fn）核心组成。DoxFILN显著提高肿瘤内CTL和NK细胞的密度和活性。从机制上讲，DoxFILN在酸性肿瘤微环境中脱壳，释放Dox-Fn和膜结合的IL15c。Dox-Fn选择性靶向癌细胞上的转铁蛋白受体，促进细胞内阿霉素释放并诱导免疫原性细胞死亡。同时，膜结合的IL15c识别并激活IL15受体β/γc异二聚体，导致CTL（分别增加16倍和28倍）和NK细胞（分别增加37倍和50倍）的增殖和激活显著增加。这里介绍的展示IL15的纳米囊泡有望成为癌症免疫化学治疗的潜在平台。
