To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic‐gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL‐10)+ EVs to promote M2 polarization of macrophage, and SRY‐box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose‐of‐action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)‐sensitive self‐assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl‐hydrogel microspheres (PGE), respectively. These materials are mixed to form a “microspheres‐in‐gel” KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL‐10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor‐α and IL‐1β levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti‐inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic‐gates strategies for OA treatment.

中文翻译：

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双细胞外囊泡时空释放在骨关节炎治疗中的基于逻辑的策略

为了有效治疗骨关节炎（OA），必须先减少现有的炎症，然后才能修复软骨损伤；这是单一类型的细胞外囊泡（EV）无法实现的。在这里，提出了一种具有逻辑门功能的水凝胶复合物，可以时空控制释放两种类型的 EV：白细胞介素 10 (IL-10)+EV 促进巨噬细胞 M2 极化和 SRY-box 转录因子 9 (SOX9)+EV 增加软骨基质合成。经过作用剂量筛选后，将双 EV 分别装入基质金属蛋白酶 13 (MMP13) 敏感的自组装肽水凝胶 (KM13E) 和聚乙二醇二丙烯酸酯/明胶甲基丙烯酰水凝胶微球 (PGE) 中。这些材料混合形成“凝胶微球”KM13E@PGE 系统。在体外，KM13E@PGE 突然释放 IL-10+电动汽车 3 天后缓慢释放 SOX9+电动汽车使用超过 30 天。在体内，KM13E@PGE 增加了 CD206+滑膜组织中 M2 巨噬细胞的比例降低，肿瘤坏死因子-α 和 IL-1β 水平降低。炎症消退后，软骨组织中的聚集蛋白聚糖和 SOX9 表达显着升高。仅使用抗炎或软骨修复疗法无法实现这种性能。本研究提供了一种可注射的集成递送系统，具有双 EV 的时空控制释放，并可能激发 OA 治疗的逻辑门策略。