Bhatta Rimsha, Han Joonsu, Liu Yusheng, Bo Yang, Wang Yueji, Nguyen Daniel, Chen Qian, Wang Hua
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nat Commun. 2025 Apr 22;16(1):3781. doi: 10.1038/s41467-025-59278-0.
Extracellular vesicles (EVs) have been actively explored for therapeutic applications in the context of cancer and other diseases. However, the poor tissue retention of EVs has limited the development of EV-based therapies. Here we report a facile approach to fabricating injectable EV hydrogels with tunable viscoelasticity and gelation temperature, by metabolically tagging EVs with azido groups and further crosslinking them with dibenzocyclooctyne-bearing polyethylene glycol via efficient click chemistry. One such EV gel has a gelation temperature of 39.4 °C, enabling in situ gelation of solution-form EVs upon injection into the body. The in situ formed gels are stable for over 4 weeks and can attract immune cells including dendritic cells over time in vivo. We further show that tumor EV hydrogels, upon subcutaneous injection, can serve as a long-term depot for EV-encased tumor antigens, providing an extended time for the modulation of dendritic cells and subsequent priming of tumor-specific CD8 T cells. The tumor EV hydrogel also shows synergy with anti-PD-1 checkpoint blockade for tumor treatment, and is able to reprogram the tumor microenvironment. As a proof-of-concept, we also demonstrate that EV hydrogels can induce enhanced antibody responses than solution-form EVs over an extended time. Our study yields a facile and universal approach to fabricating injectable EV hydrogels with tunable mechanics and improving the therapeutic efficacy of EV-based therapies.
细胞外囊泡（EVs）已被积极探索用于癌症和其他疾病的治疗应用。然而，EVs在组织中的保留较差限制了基于EVs的疗法的发展。在此，我们报告了一种简便的方法来制备具有可调粘弹性和凝胶化温度的可注射EV水凝胶，即通过用叠氮基代谢标记EVs，并通过高效的点击化学将它们与带有二苯并环辛炔的聚乙二醇进一步交联。一种这样的EV凝胶的凝胶化温度为39.4°C，能够在注射到体内后使溶液形式的EVs原位凝胶化。原位形成的凝胶在4周以上保持稳定，并且随着时间的推移能够在体内吸引包括树突状细胞在内的免疫细胞。我们进一步表明，肿瘤EV水凝胶在皮下注射后，可以作为包裹EV的肿瘤抗原的长期储存库，为树突状细胞的调节和随后肿瘤特异性CD8 T细胞的启动提供更长的时间。肿瘤EV水凝胶在肿瘤治疗中还显示出与抗PD-1检查点阻断的协同作用，并且能够重新编程肿瘤微环境。作为概念验证，我们还证明，与溶液形式的EVs相比，EV水凝胶在更长的时间内能够诱导增强的抗体反应。我们的研究产生了一种简便且通用的方法来制备具有可调力学性能的可注射EV水凝胶，并提高基于EVs的疗法的治疗效果。
