Advanced Hybrid Polysaccharide—Lipid Nanocarriers for Bioactivity Improvement of Phytochemicals from Centella asiatica and Hypericum perforatum

<b>Background/Objectives:</b> Phytochemicals are known to be active contributors to a healthy life, providing valuable wound healing benefits. <b>Methods:</b> This research took an innovative approach that successfully overcame the bioavailability limits of herbal extracts, by entrapping <i>CentellaA</i> with <i>HypericumP</i> in nanostructured lipid carriers (NLCs) and hybrid hyaluronic acid (HA-NLCs) as valuable formulations with enhanced bioactivity. <b>Results:</b> NLCs and HA-NLCs showed excellent entrapping efficiency values for <i>CentellaA</i> and <i>HypericumP</i> ranging from 89.5 to 95.3%. Co-entrapping of <i>CentellaA:HypericumP</i> in a weight ratio of 4:1 and 2:1 led to diameters of 221.4 ± 2.08 nm for NLC-<i>CentellaA-HypericumP</i> and 220.3 ± 1.74 nm for hybrid HA-NLC-<i>CentellaA-HypericumP</i>. The bimodal calorimetric profile of NLCs contributed to a lower degree of lipid core structural organization. HA-NLC-<i>CentellaA</i> showed the safest biocompatibility behavior with BJ skin cells. <b>Conclusions:</b> The cells treated with NLC-<i>CentellaA</i> exhibited a favorable scratch wound closure and promoted the fastest BJ cell migration. NLC- and HA-NLC herbal extracts remodeled the cytoskeleton of BJ fibroblast cells. The morphological fluorescence changes revealed that the fibroblast cells retained intact their cytoskeleton, characteristic of a viable cell with no obvious stress. An active motility of cells treated with NLCs in the wound area was detected, indicating strong pro-migratory properties; e.g., for NLC-<i>CentellaA</i>, the wound was almost closed after 30 h. Designing NLCs with HA adaptability to reinforce the skin wound healing action represents a desired step for the development of herbal products that meets the challenge of combining the benefits of phytochemicals and nanotechnology to create value-added herbal products.