Lipidic Prodrug Co‐Crystals: A Platform for Combination Therapy Targeting Fungal Biofilms

Abstract Fungal infections are often complicated by biofilm formation and concurrent inflammation, limiting the efficacy of conventional antifungal therapies. To address these challenges, we developed a novel hybrid drug delivery platform—lipidic prodrug co‐crystals (LPCCs)—that combines the benefits of lipidic self‐assembly and pharmaceutical co‐crystallization. In this study, a lipidic prodrug is synthesized by linking catechol‐containing α‐aminophosphonate with phenylboronic acid‐modified bifonazole (Bfz), an antifungal agent, via boronate bonding. The resulting self‐assembled structures exhibit high drug‐loading capacity (up to 85%) and are capable of co‐crystallizing with anti‐inflammatory agents such as nonsteroidal antiinflammatory drugs (NSAIDs) through strong aromatic and ionic interactions. This dual‐delivery system enables the controlled, site‐specific release of both antifungal and anti‐inflammatory agents in response to the acidic and oxidative microenvironment of fungal biofilms. LPCCs effectively prevent biofilm formation, eradicate mature biofilms, and enhance ROS‐scavenging capacity. Mechanistically, LPCCs inhibit the NF‐κB/COX‐2 pathway, reduce pro‐inflammatory cytokines, and promote an anti‐inflammatory M 2 macrophage phenotype. In a murine rectal candidiasis model, LPCCs significantly reduced fungal load, restored tissue integrity, and normalized immune and microbial environments. Our findings highlight LPCCs as a promising strategy for enhancing treatment efficacy, improving patient compliance, and overcoming the limitations of current antifungal therapies.