## 3 Nanosized-Lipid-Based Drug Delivery Systems in Wound Healing
The skin has an essential protective function against aggressive environmental factors, but it also prevents the penetration of topical agents. The skin's primary barrier is the stratum corneum, which is formed by corneocytes and a lipid-rich matrix (chain ceramides, free fatty acids and cholesterol). It counteracts the penetration of most hydrophilic and macromolecular drugs into the skin. Given that the stratum corneum is impenetrable for most drugs, nanosized-lipid-based drug delivery systems represent a biochemical strategy to deliver both hydrophilic and hydrophobic drugs into the skin [28]. An active topical substance can penetrate the skin through three pathways: intracellular, intercellular and transfollicular pathways [67]. Liposomes penetrate the skin as an intracellular delivery system and deposit the drugs into the outer layer of the skin, providing prolonged release of the drug [68]. Moreover, they cover the wound and maintain a moist environment at the wound's surface, promoting healing [69]. On the other hand, elastic liposomes and transfersomes squeeze through the intercellular parts of the corneous layer, being able to penetrate intact skin [70]. Ethosomes, due to the presence of ethanol, are soft, malleable vesicles able to penetrate stratum corneum lipids through fluidization, delivering active substances beneath the corneous layer [32]. The reported data exhibit intercellular and transcellular pathways as drug delivery mechanisms of ethosomes [71]. Various studies revealed that nanoparticles might prefer transfollicular and intercellular pathways for skin penetration [72, 73, 74, 75]. Moreover, the transfollicular route can supply a deeper penetration of the active substances than the intracellular pathway [76]. In addition, solid lipid nanoparticles express prolonged contact with the corneous layer lipids, facilitating better penetration of liposoluble substances. On the other hand, nanostructured lipid carriers, due to the presence of the liquid lipid in the matrix, are associated with a higher amount of drug skin deposition [77]. Furthermore, lipid nanoparticles can maintain skin hydration due to an occlusive biofilm formed at the surface of the stratum corneum, and its adhesion to the corneous layer stimulates regeneration of the skin lipid film. Moreover, this formed protective lipid film enhances the penetration of the active substances into the skin [41]. The reported data express that nanoparticles with a size less than 20 nm can potentially permeate intact and injured skin, and those with a size less than 45 nm but higher than 21 nm can penetrate only injured skin [78, 79, 80]. The anatomical target sites of nanosized-lipid-based drug delivery systems and their penetration pathways into the skin are presented in Figure 3.  
In the following sections, we will detail the most relevant studies regarding the role of vesicular systems and lipid nanoparticles in wound care, with the most important results being presented in Tables 1 and 2. Figure 3: Schematic illustration of the anatomical target sites and skin penetration pathways of the nanosized-lipid-based drug delivery systems. Liposomes penetrate as an intracellular delivery system and deposit the drugs into the stratum corneum. They have poor penetration of the drug into the dermis. Transfersomes squeeze through the intercellular parts of the corneous layer or penetrate through the transfollicular pathway to release the drug into the dermis. Ethosomes penetrate stratum corneum lipids through fluidization, using transfollicular or intercellular pathways and releasing the drug into the dermis. Nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) penetrate through intercellular and transfollicular pathways into the dermis. \begin{table}
\begin{tabular}{c c c c c c c c} \hline \multicolumn{6}{c}{**Properties**} \\
**Drug Loaded in** & **PS = Particle Size (nm)** & **Experimental Design** & **Administration** & **Effects** & **Refs.