Healing the Sole: Combining Natural Plant Extracts and Conventional Drugs in Wound Delivery Systems for Diabetic Foot Ulcer Treatment

Diabetic foot ulcers (DFUs) affect 19–34% of diabetic patients with a five-year mortality rate of 50–70%. It is characterized by a high infection risk, chronic inflammation, oxidative stress, and poor angiogenesis, rendering existing therapies inadequate, which causes antimicrobial resistance and amputations. Bioactive compounds, such as curcumin, flavonoids, tannins, polyphenols, and proteins, found in natural product extracts (NPEs) have antibacterial, anti-inflammatory, antioxidant, and regenerative properties but are prone to variability and instability. Conventional drugs can be applied for targeted infection management and metabolic modulation, but lack regenerative capacity. The combined and synergistic potential of these two agents has not received much attention, especially when integrated into advanced drug delivery systems (DDSs), such as microneedles, hydrogels, nanofibers, and smart bandages. This review discusses NPEs, conventional drugs, combinations, and integration into DDSs, based on wound characteristics. These include depth, infection status, exudate level, and perfusion, as recommended by the 2023 IWGDF guidelines. Three combinations have shown promise in preclinical studies: propolis-charcoal bandages, propolis-oregano microneedles, and Centella-ZnO nanocomposites. However, none have yet been validated in clinical settings, and barriers to clinical adoption persist—standardization, stability, and regulatory issues. This work aims to pave the way for more accessible, sustainable, and efficacious DFU therapeutics by bridging natural and conventional approaches.