Lipidic prodrug nanosponges deliver proteins for combination therapy of candida-biofilm infections

Abstract

Lipidic prodrug nanomedicines combine the benefits of nanoparticles and prodrugs, yet their use in conjunction with protein therapeutics has been restricted by the subpar loading and protective capabilities of traditional lipidic prodrug assemblies. To address this challenge, this study introduces lipidic prodrug nanosponges (LPNs) for the loading and protection of proteins, aiming for combination therapy of chemical and protein therapeutics. A ketoconazole-containing lipidic prodrug is synthesized via dynamic boronate bond formation and subjected to assemble to form the nanosponge structures. Regardless of their isoelectric points and molecular weights, proteins can be efficiently loaded into LPNs, achieving a loading efficiency of approximately 60 % due to multivalent interactions. Additionally, LPNs effectively shield proteins from degradation and enable controlled release. Subsequently, the representative DNase I-loaded LPNs effectively prevent the formation of Candida biofilm and destruct mature biofilms through the combined action of DNase I, which eliminates extracellular DNA in the biofilm matrix, thereby enhancing the antifungal efficacy of ketoconazole in combination. Furthermore, DNase I-loaded LPNs efficiently eradicate Candida biofilms and alleviate inflammation in murine models of oral candidosis and model candidal vaginitis, facilitating tissue remodeling. Overall, our LPNs offer an efficient and protective platform for protein delivery in combination therapy.