## 4 Future Perspectives  
Nanosized-lipid-based drug delivery systems have proven to be an area of active research in wound care, providing efficient topical formulations in different types of wounds such as burn wounds or diabetic chronic wounds. However, new innovative approaches are needed to overcome current limitations. Nanosized-lipid-based drug delivery systems have been validated for nucleic acid delivery in many areas of medical research, such as oncology, rare diseases or infectious diseases, enabling the release of the first commercial synthetic short interfering RNA (siRNA) drug [175; 176; 177]. Furthermore, ionizable cationic lipid nanoparticles were a breakthrough in these fields, overcoming previous issues with delivering siRNA into cells. Nucleic acids such as microRNA or siRNA have essential roles in wound-healing phases, such as promoting keratinocyte growth, regulating the inflammatory process, angiogenesis and promoting proliferation, and they have been correlated with abnormalities in their regulations concerning chronic wounds or abnormal scars [176; 178]. Many different types of microRNA can be used in wound care, targeting pathways involved in scarless healing such as transforming growth factor \(\beta\) or SMAD proteins [179; 180; 181]. As we previously stated, several studies have explored lipid nanoparticles loaded with nucleic acids in wound care. A topical treatment for diabetic wound healing was optimized using cationic lipid nanoparticles combined with an edge activator sodium cholate, resulting in a stable lipoproteingeplex nanoparticle to increase the topical delivery of siRNA [97]. However, the precise mechanism of the cellular uptake of nucleic acids is still unknown. That notwithstanding, some studies reported that the size of the nanoparticle might influence the mechanism. For instance, a size range between 4 and 10 nm leads to direct penetration of the nanoparticles through the cell membrane compared with particles with a size range between 10 and 120 nm, which may be delivered through endocytosis [182]. In vivo research on diabetic mice showed excellent penetration of the siRNA nanoparticle in the target site with an ongoing deposition of the substance five days after administration, which led to accelerated wound closure. Another important aspect was the low cytotoxic in vivo effect of the formulation, making it a safe and viable form of treatment of a diabetic wound [97]. Another approach to lipid nanoparticles loaded with nucleic acids was to develop an excellent formulation for chronic ischemic wounds associated with peripheral vasculopathy and a high level of micro-RNA-210. This formulation succeeded in decreasing the level of micro-RNA-210, which has been correlated with a reduced rate of keratinocyte proliferation [183]. Furthermore, the same research group explored the application of topical, lyophilized, keratinocyte-targeted lipid nanoparticles loaded with locked nucleic acid-modified anti-microRNA in burn wound therapy. The results of the in vivo studies on mice exhibited an accelerated wound closure rate. It should be noted that in this formulation, the lipid nanoparticles were lyophilized to extend the storage stability [184]. Another study previously presented showed the important role of micro-RNA-132 in wound healing [99]. Based on their essential role in maintaining an optimal wound healing environment, topically delivering nucleic acids can be a suitable formula in wound care to avoid systemic toxicity and maximize therapeutic potential [185; 186; 187]. However, further in vivo research in this field should be embraced, including nanosized-lipid-based drug delivery systems. Another interesting topic for further research is the lipid-polymer hybrid nanoparticle (LPN) technology. This novel technology combines the liposome and polymeric nanoparticle properties formed by a core-shell structure with a lower rate of drug leakage, high bioavailability and storage stability [188].