靶向衰老细胞的纳米疗法改善纤维化并克服肿瘤免疫排斥
Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
组织和肿瘤的纤维化重构会形成免疫抑制微环境，导致器官功能障碍，并限制肿瘤对免疫治疗的应答。衰老样细胞是纤维化的保守驱动因素和治疗靶点，但其功能异质性使干预困难。研究者发现P-选择素表达于纤维化组织和肿瘤中一部分衰老样细胞表面，于是利用能结合P-选择素的褐藻多糖纳米颗粒，开发出衰老调节纳米颗粒（SMNP），选择性靶向这些疾病相关状态。SMNP表现出强效抗纤维化和免疫调节作用，同时提高了治疗指数。机制上，体内功能性靶标被鉴定为一种致病性、免疫抑制性巨噬细胞群体。在纤维化肿瘤中，微环境重塑恢复了免疫浸润，并使肿瘤对免疫检查点治疗敏感。该策略有望跨纤维化和癌症通用。
为什么推荐给您：提出靶向P-选择素阳性衰老样细胞的新纳米平台，在动物模型中同时改善纤维化和免疫治疗应答。
不需要生物学背景，多打比方
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摘要Abstract
Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.