The persistence of non-healing diabetic wounds is frequently attributed to excessive inflammation and bacterial infections. Therefore, strategies that target the reduction of inflammation while simultaneously inhibiting bacterial proliferation may offer an effective approach to overcoming this clinical challenge. In this study, we have developed an innovative formulation of hyaluronic acid (HA)-based dissolving microneedles (Cu(II)-PDA/ORI MNs) that incorporate oridonin (ORI) and Cu(II)-PDA nanoparticles, specifically designed for the treatment of chronic wounds in diabetic murine models. Our findings demonstrate that the composite MNs exhibit robust mechanical properties, facilitate drug delivery to the deeper layers of the skin, and exhibit favorable cytocompatibility and hemocompatibility. The encapsulation of ORI within the MNs effectively modulates the phenotype of RAW264.7 macrophages and exhibits significant anti-inflammatory properties, thereby contributing to the reduction of excessive inflammation within the wound microenvironment. Cu(II)-PDA nanoparticles significantly mitigate the toxicity associated with Cu(II) while retaining substantial antibacterial efficacy. Furthermore, they effectively promote wound angiogenesis, thereby expediting the wound healing process. Consequently, these Cu(II)-PDA/ORI MNs emerge as promising candidates for multifunctional wound dressing applications.
Background 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.
Lipid–polymer hybrid nanoparticles (LPNs) have emerged as promising nanocarriers for oral delivery of poorly water-soluble drugs because they combine the advantages of polymeric and lipid-based nanoparticles. However, rational surface engineering of LPNs to reduce clearance in the gastrointestinal tract and improve bioavailability remains a challenge. Modification of LPNs with wheat germ agglutinin (WGA), a specific bioadhesive material, was hypothesised to increase site-specific adhesion and improve bioavailability. This study focused on the preparation and characterisation of WGA-modified LPNs (WGA-LPNs) for oral delivery of oridonin. WGA-LPNs were produced by incubating synthetic WGA-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine with LPNs, which had been formed using nanoprecipitation. The WGA-LPNs had a particle size of 326.7 ± 5.2 nm and a zeta potential of −31.8 ± 1.04 mV. The core–shell structure and the WGA binding were confirmed by immune gold labelling electron microscopy. Approximately 80% of the drug was released from the nanoparticles within 24 h. WGA-LPNs showed efficient binding to both Caco-2 and HT29-MTX cells and underwent receptor-mediated endocytosis, as evidenced by cellular uptake and confocal imaging. In addition, coumarin 6-loaded WGA-LPNs showed enhanced uptake in the ligated intestinal loop model in vivo, probably due to improved bioadhesion to the villi. These results suggested that WGA-LNPs showed increased intestinal bioadhesion and cellular uptake and have the potential to improve the oral delivery of poorly water-soluble drugs.
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