Fungal infections often accompany the formation of biofilms and concurrent inflammation, which limits the efficacy of traditional antifungal therapies. To address these challenges, we developed a novel hybrid drug delivery platform - lipid prodrug co-crystal (LPCC), which combines the advantages of lipid self-assembly and drug co-crystallization. In this study, a lipid prodrug was synthesized by linking an α-amino phosphonic acid salt containing catechol with a benzylborate-modified antifungal agent, benzylborate-modified bifenazone (Bfz), through a boronic acid bond. The resulting self-assembled structure exhibited high drug loading capacity (up to 85%) and was able to form a co-crystal with anti-inflammatory agents (such as non-steroidal anti-inflammatory drugs (NSAIDs)) through strong aromatic and ionic interactions. This dual delivery system can control the site-specific release of antifungal agents and anti-inflammatory agents in response to the acidic and oxidative microenvironment of the fungal biofilm. LPCCs can effectively prevent biofilm formation, eradicate mature biofilms, and enhance the ability to clear ROS. Mechanistically, LPCC inhibits the NF-κB/COX-2 pathway, reduces pro-inflammatory cytokines, and promotes the anti-inflammatory M2 macrophage phenotype. In a mouse rectal candidiasis model, LPCC significantly reduced fungal load, restored tissue integrity, and normalized the immune and microbial environment. Our research results emphasize that LPCC is a promising strategy that can improve treatment efficacy, enhance patient compliance, and overcome the limitations of current antifungal therapies. This research was published under the title "Lipidic Prodrug Co-Crystals: A Platform for Combined Therapy Targeting Fungal Biofilms" in Advanced Materials.
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DOI: 10.1002/adma.202510382