Diabetes, one of the global metabolic disorders, is often associated with delayed wound healing due to the elevated level of free radicals at the wound site, which hampers skin regeneration. This study aimed at developing a curcumin-loaded self-emulsifying drug delivery system (SEDDS) for diabetic wound healing and skin tissue regeneration. For this purpose, various curcumin-loaded SEDDS formulations were prepared and optimized. Then, the SEDDS formulations were characterized by the emulsion droplet size, surface charge, drug content/entrapment efficiency, drug release, and stability. In vitro, the formulations were assessed for the cellular uptake, cytotoxicity, cell migration, and inhibition of the intracellular ROS production in the NIH3T3 fibroblasts. In vivo, the formulations’ wound healing and skin regeneration potential were evaluated on the induced diabetic rats. The results indicated that, after being dispersed in the aqueous medium, the optimized SEDDS formulation was readily emulsified and formed a homogenous dispersion with a droplet size of 37.29 ± 3.47 nm, surface charge of −20.75 ± 0.07 mV, and PDI value of less than 0.3. The drug content in the optimized formulation was found to be 70.51% ± 2.31%, with an encapsulation efficiency of 87.36% ± 0.61%. The SEDDS showed a delayed drug release pattern compared to the pure drug solution, and the drug release rate followed the Fickian diffusion kinetically. In the cell culture, the formulations showed lower cytotoxicity, higher cellular uptake, and increased ROS production inhibition, and promoted the cell migration in the scratch assay compared to the pure drug. The in vivo data indicated that the curcumin-loaded SEDDS-treated diabetic rats had significantly faster-wound healing and re-epithelialization compared with the untreated and pure drug-treated groups. Our findings in this work suggest that the curcumin-loaded SEDDS might have great potential in facilitating diabetic wound healing and skin tissue regeneration.

Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical efficacy is limited by multidrug resistance (MDR), poor tumor penetration, and off-target toxicity. To address these challenges, we developed matrix metalloproteinase (MMP)-responsive multiwalled carbon nanotubes (MWCNTs) for tumor-targeted DOX delivery. The MWCNT formulation exhibited MMP-responsive cellular uptake, cell permeability, tissue penetration, and enhanced cytotoxicity of loaded DOX in cancer cells, a transwell model, and tumor spheroids. Mechanistic studies revealed that these CNTs entered cells primarily via clathrin-mediated endocytosis. Acidic endosomal conditions promoted lipid redistribution and membrane destabilization of endolysosomes, facilitating efficient endosomal escape and strong colocalization with the endoplasmic reticulum (ER). This intracellular trafficking pathway bypassed drug efflux mechanisms and prolonged intracellular drug retention in MDR cancer cells. In a mouse breast tumor model, MMP-responsive MWCNTs demonstrated prolonged systemic circulation with approximately 5-fold higher blood DOX levels and 2-fold greater tumor accumulation than free DOX. Improved pharmacokinetics and tumor specificity enhanced DOX’s tumor inhibitory effects and increased tumor cell apoptosis. Importantly, the MMP-responsive MWCNTs significantly reduced DOX’s off-target toxicity, as evidenced by approximately 2-fold lower cardiac DOX accumulation, reduced cardiomyocyte apoptosis, and preservation of white blood cell counts. Overall, this MMP-responsive CNT-based nanoplatform offers a promising strategy to enhance tumor targeting and retention, overcome MDR, and improve the therapeutic index of DOX.