Dendritic Nanogels Directed Dual‐Encapsulation Topical Delivery System of Antimicrobial Peptides Targeting Skin Infections

Antimicrobial peptides (AMPs) are promising antibacterial agents in the fight against multidrug resistant pathogens. However, their application to skin infections is limited by the absence of a realizable topical delivery strategy. Herein, a hybrid hierarchical delivery system for topical delivery of AMPs is accomplished through the incorporation of AMPs into dendritic nanogels (DNGs) and their subsequent embedding into poloxamer gel. The high level of control over the crosslink density and the number of chosen functionalities makes DNGs ideal capsules with tunable loading capacity for DPK‐060, a human kininogen‐derived AMP. Once embedded into the poloxamer gel, DPK‐060 encapsulated in DNGs displays a slower release rate compared to those entrapped directly in the gels. In vitro EpiDerm Skin Irritation Tests show good biocompatibility, while MIC and time‐kill curves reveal the potency of the peptide toward Staphylococcus aureus. Anti‐infection tests on ex vivo pig skin and in vivo mouse infection models demonstrate that formulations with 0.5% and 1% AMPs significantly inhibit the growth of S. aureus. Similar outcomes are observed for an in vivo mouse surgical site infection model. Importantly, when normalizing the bacteria inhibition to released/free DPK‐060 at the wound site, all formulations display superior efficacy compared to DPK‐060 in solution. An advanced topical delivery strategy for antimicrobial peptides (AMPs) is developed by integrating dendritic nanogels (DNGs) into poloxamer gel. Upon encapsulation of DPK‐060 by DNGs, the hybrid system enables controlled release of the peptide molecules and enhances their potency toward Staphylococcus aureus inoculated skin infection models both in vitro and in vivo.