One of the most significant symptoms in type 2 diabetic patients is chronic diabetic foot ulcers (CDFU). It is crucial in limiting the patient's mobility, diminishing the quality of life, and, unfortunately, can lead to lower limb amputation if incorrectly treated [1,2]. Almost 15–25 % of diabetic patients may experience these chronic ulcers, while 15–20 % of DFU patients will end up with the need for lower limb amputation [[3], [4], [5]]. CDFU are very resistant to medical treatment. Additionally, they take several weeks to heal and are very liable to be infected [6]. CDFU healing has a spontaneous biological regeneration mechanism, which is naturally occurring to restore skin structural integrity and regenerate injured skin tissues [7]. Generally, the wound healing process is established through complex synchronized integrated mechanisms such as hemostasis, inflammation, growth, re-epithelialization, and remodeling [8,9]. Furthermore, anomalies in the healing process such as oxygen level, chemokines, mechanical factors, extracellular matrix, growth factor synthesis, fibrosis, immunopathy, neuropathy, vasculopathy, and bacterial growth also have a direct impact on wound healing mechanism and tissue regeneration that could lead to failure of prompt wound healing [9,10]. DFU patients are susceptible to frequent infections, loss of sensation in peripheral limbs, and excessive inflammation [11]. The bacterial burden of the wound, especially Staphylococcus Aureus Methicillin Resistance (MRSA), which is resistant to various antibiotics, can lead to excessive inflammation and consequently may hinder the mechanism of healing [12]. New advances have been adopted to treat CDFUs, one of which is nanotechnology, which has been proven to be a reliable and efficient approach [6]. Resveratrol (3, 5, 4-trihydroxy-trans-stilbene), RES, is a potent natural polyphenolic substance with a very powerful antioxidant and anti-inflammatory activity. RES is found naturally in two isomeric forms (active form trans-RES and inactive form cis-RES) [13,14]. RES has gained a lot of interest in the last decade due to its wide therapeutic activity. RES can support vascular [15], heart health [16,17], cognitive [18,19], mental performance [20], mineralization [21], physical activity [22], anticancer [23], antioxidant; anti-inflammatory [24,25], anti-aging as well as skin whitening [24]. Despite all these biological benefits, RES (M.Wt: 228.25; Fig. (1)) still has several formulation challenges due to its unfavorable physiochemical properties. RES with low water solubility (≈0.05 mg/mL), photosensitivity, chemically instable in alkaline pH and high temperature. Its relative oral absorption is ≈ 70 % [26]. However, it is subjected to extensive first-pass metabolism that influences its bioavailability (<1 %). Thus, a crucial need was employed to develop a novel and alternative drug delivery strategy to benefit from RES's therapeutic potential.

RES topical application is considered a very attractive and appropriate route of administration because of its antioxidant, anti-aging effect, and protective effects against UV exposure. Strategies involving an increase in RES through stratum corneum (SC), enhancing the stability of RES, and increasing RES diffusion and permeation through SC, epidermal, and sub-epidermal layers will possibly enhance the therapeutic effectiveness of RES [27,28]. Nanotechnology has significantly improved the topical drug delivery of RES. Multiple approaches were used including micro/nano-emulsions [29]; noisomes [30]; ethosomes [31]; nanosponges [32]; micro-particles [33]; nanoparticles [34]; and glycerosomes [35]. Vesicular drug delivery systems appear to be the most promising strategy. Glycerosomes are a novel approach to boost liposomal function in dermally and trans-dermally drug delivery systems by modifying the bilayer fluidity of liposomes [36]. They are highly ordered assemblies of phospholipids that comprise the use of glycerol in high concentrations (10–30 V/V %). Glycerol is a non-toxic short-chain alcohol that acts as a humectant, emollient, and penetration enhancer for skin layers [35]. Thus, Glycerosomes are considered a completely acceptable and safe form for topical use [37]. Compared to traditional liposomes, glycerosomes transport phytochemicals, increasing their skin bioavailability [38]. Glycerosomes can contribute to the accumulation of phytochemicals in different layers of the skin, mainly due to the moisturizing effect of glycerol, which can change the ordered structure of the stratum corneum and promote the passage of active compounds [39]. The objective was to develop RES-loaded glycerosomal nanovesicles utilizing phospholipid (S75), stabilizer (cholesterol), surfactant (tween 80), and glycerol as penetration enhancer. Loaded nanovesicles were then incorporated in HPMC K 15 gel to facilitate application and prolong retention time at the targeted area. A fully in vitro characterization and in vivo study was planned to be performed to assess the efficacy of the formulation.