Internal-External Homologous Drug-Loaded Exosome-Like Nanovesicles Released from Semi-IPN Hydrogel Enhancing Wound Healing of Chemoradiotherapy-Induced Oral Mucositis

Xiangjuan Wei,1,* Mengyuan Wang,1,* Xiaocong Dong,1 Yichen He,1 Wenbin Nan,1 Shenglu Ji,1 Mengyuan Zhao,1 Haodang Chang,1 Hongliang Wei,2 Dan Ding,3 Hongli Chen1 1Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China; 2School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, Henan, People’s Republic of China; 3Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongli Chen, Clinical Medical Center of Tissue Engineering and Regeneration, The Third Affiliated Hospital, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China, Email [email protected]: Oral mucositis (OM) is a common acute side effect among patients undergoing chemotherapy and/or radiotherapy, with complex pathogenesis and limited current treatment efficacy. Rabdosia rubescens, a traditional Chinese herb, contains oridonin (ORI) with antibacterial and anti - inflammatory properties. However, ORI’s poor solubility and low bioavailability hamper its clinical use. Medicinal plant - derived exosome - like nanovesicles (ENs) are emerging as a promising drug delivery system for wound repair. This study aimed to develop a novel therapeutic approach.Methods: We fabricated internally-externally homologous drug-loaded exosome-like nanovesicles (ORI/ENs) derived from Rabdosia rubescens and encapsulated them in a semi-interpenetrating network hydrogel system (ORI/ENs/Gel) to repair chemoradiotherapy-induced OM. The morphology, biocompatibility, and antibacterial properties were evaluated. Moreover, the proliferative and migratory capacity were measured using L929 cells. In addition, the pro-healing effects and the underlying molecular mechanisms of ORI/ENs/Gel were assessed in vivo.Results: ENs were extracted and purified from Rabdosia rubescens by sequential ultra-centrifugations. The encapsulation efficiency (EE) and loading capacity (LC) of ORI in ORI/ENs were 76.4 ± 3.2% and 9.21 ± 0.45%, respectively, suggesting that ENs had a high loading efficiency for homologous drug ORI. The evaluation of toxicity and antibacterial effects has been proven that ORI/ENs has biocompatibility and antibacterial properties. In vivo, ORI/ENs/Gel promoted collagen deposition, targeted NLRP3 to reduce inflammation, and accelerated OM wound healing.Conclusion: The hydrogel composite incorporating internally-externally homologous drug-loaded ENs offers the potential to provide targeted therapy, improve bioavailability, and promote efficient healing of the OM. Keywords: chemoradiotherapy-induced oral mucositis, exosome-like nanovesicles, oridonin, hydrogel, NLRP3