**6. Nanomaterials as delivery agents carrying therapeutic molecules**

Many therapeutic molecules such as nitric oxide, various antibiotics and antioxidative compounds, bioactive molecules, and vitamins possess great potential for wound healing. But each of these has few problems associated with solubility, stability, degradation by enzymes, temperature sensitivity, and so on. Because of these problems, the topical applicability of these compounds decreases to a large extent. Therefore, a need was felt to develop nanotechnology-based carriers to encapsulate these compounds for enhancing their efficacy.

#### **6.1 Nanoparticles containing bioactive molecules for healing**

Nanoencapsulated bioactive molecules also served as promising approach for skin tissue engineering. NPs encapsulated with bioactive ingredients help in slow and sustained release of the active moiety to the target site and increase the stability of molecules [132]. As an important natural molecule, curcumin suffers from limitations of poor solubility and fast degradation rate that hinder its applicability as an antioxidative and antimicrobial agent. To overcome these limitations, curcumin-loaded NPs have been synthesized, which enhanced the wound healing in the murine model as compared to pure curcumin [133]. In another report, efforts have been made to prepare curcumin-loaded chitosan NPs that were then impregnated into collagenalginate scaffolds. Such prepared nanoscaffolds resulted in complete epithelization and granulation tissue formation for rapid healing of wounds in diabetic mice (**Figures 2** and **3**) [134]. An important study demonstrated the effect of guanidinylated chitosan NPs loaded with five different bioactive molecules (EGF, ascorbic acid, hydrocortisone, insulin, and 1,25-dihydroxyvitamin D3). These biomolecules are beneficial for stimulating skin fibroblasts and keratinocyte proliferation but have limited applicability as they are unstable in wound dressing fabrication and storage. The prepared wound dressings resulted in stable delivery of bioactive factors and enhancement of skin wound healing in Wistar rats [135]. In a similar study, curcumin NPs were embedded in gelation microsphere hydrogels. These thermosensitive and MMP-9 responsive hydrogels induced drug release at the wound bed and resulted in acceleration of diabetic skin wound healing due to their ability to promote cell migration and antioxidant nature [136].

Another important flavonoid, quercetin, is also known for its antioxidant nature. But its topical application is limited due to low solubility, low stability, and less release after application. To overcome these limitations, quercetin was encapsulated into mesoporous silica NPs carrying a copolymer. These NPs showed thermoresponsive behavior that acts to provide the potential of such particles in dermal delivery [137]. In another study, topical application of chitosan-fibrin scaffolds impregnated with quercetin significantly accelerated the process of wound healing [138]. Similarly, baicalinloaded nanohydrogels comprised of a dispersion of cholesterol-derivatized gellan in phosphate buffer. Baicalin (a flavone glycoside)-loaded nanohydrogels demonstrated complete skin restoration and inhibition of specific inflammatory markers causing rapid skin wound healing in *in vivo* mice [139].
