## 2 Nanosized-Lipid-Based Drug Delivery Systems  
Nanosized-lipid-based drug delivery systems have demonstrated substantial capabilities for dermal and transdermal drug administration. They consist of biocompatible and biodegradable lipids that accomplish controlled release, targeted delivery and drug protection. These drug delivery systems have emphasized the capacity to enclose a multitude of therapeutic agents, including growth factors, gene therapy or cytokines [30; 31; 32].  
It is known that intact skin acts as a barrier against the penetration of topical formulations. Moreover, studies have reported poor permeability of drug molecules even in damaged skin [33; 34], enforcing the importance of developing novel delivery systems in order to attain the specific target layer of the skin.  
Among the most promising possibilities of overcoming these issues, nanosized-lipid-based drug delivery systems can provide unique properties for delivering drug molecules in the targeted areas and improve skin wound healing. They are classified as vesicular systems and lipid nanoparticles [35; 36] (see Figure 1). Furthermore, we emphasize their structures in Figure 2.  
Vesicular systems consist of amphiphilic molecules, owing to the presence of a polar or hydrophilic region (head) and a nonpolar or lipophilic region (tail), and these can be further categorized into liposomes, ultra-deformable liposomes and ethosomes [35; 37].  
Regarding the properties of lipid vesicles, their sizes vary from 40 to 800 nm, which allows them to cling to the lipid matrix of the corneous layer and increase the amount of drug molecules that penetrate the deeper skin layers. It is noteworthy that the vesicles' particle sizes influence drug delivery into the skin. The maximum delivery of molecules has been shown in vesicles with a size \(\leq\)70 nm [32; 37; 38].  
A growing interest has been directed toward lipid nanoparticles [39] which, based on recent findings, are superior to vesicular systems, as they exhibit better penetration into the deeper layers of the epidermis [32]. Research in lipid nanoparticles has increased considerably given their advantages, especially the smaller size, deeper skin penetration and improved cost-effectiveness. Moreover, they allow the inclusion of biocompatible components approved for pharmaceutical and cosmetic use, incorporating molecules with varying solubility, increased diffusion through the skin by combination with physical and mechanical enhancers, targeted delivery and decreased systemic side effects [40].  
Lipid nanoparticles are categorized into solid nanoparticles (SLNs), which can be an alternative to traditional lipid-based formulations such as liposomes and emulsions [41], and a second generation named nanostructured lipid carriers (NCLs), an improved version of SLNs [24]. The complex lipid matrix of the NCLs, including liquid lipids (oils), generates changes in the structure of the solid lipids, leading to a less ordered crystalline arrangement that averts drug leakage and supplies a higher drug load compared with SLNs, which are formed only by solid lipids and a matrix with no imperfections [42; 43]. In addition, properties such as the size of the lipid nanoparticles influence their type of delivery. For instance, particles smaller than 10 nm can directly pass through the stratum corneum of viable human skin, while larger particles between 10 nm and 200 nm access the skin via hair follicle openings [44]. Furthermore, the composition of the physiological lipids of the lipid nanoparticles enhances the rearrangement and fluidization of the stratum corneum lipid matrix, leading to better permeability of drug molecules. Moreover, their occlusion effect can prevent water loss, leading to enhanced skin hydration [24; 45].  
Figure 1: Characteristics of nanosized-lipid-based drug delivery systems applied in wound care.