One-component lipidic bicontinuous nanospheres as a smart drug loading platform to eradicate candida biofilms in oral and vaginal infection

Bicontinuous nanospheres (BCNs) with a highly twisted network of hydrophobic phases interwoven with a network of hydrated hydrophilic parts are essential for the loading and releasing of therapeutics. However, a facile methodology to construct BCNs with a single lipid molecule is still challenging. Here we report the synthesis of X-shaped lipids that can self-assemble into stable one-component sponge-phase BCNs without the assistance of any stabilizers as a platform for drug delivery. The X-shaped lipids with two hydrophilic heads and two hydrophobic tails are formed via dynamic covalent boronate between the phenylboronic acid-modified polar head and the catechol-containing lipids with different carbon chain lengths. This methodology provides an efficient and convenient way to synthesize lipids with different architectures, and their possibility in fabrication BCNs was further screened. The representative miconazole-loaded prodrug BCNs possess high drug loading content, up to 41.6%, and a fast, zero-order drug release profile after exposure to an acidic/oxidative microenvironment, such as Candida albicans biofilm. Also, the carbon chain lengths of lipids affect the prodrug BCNs' formation and interactions with fungal membranes. The optimal prodrug BCNs with 10-carbon chains hold superb Candida biofilm eradication efficacy in vitro and in vivo without affecting the normal tissues. Therefore, our strategy provides a facile methodology to construct BCNs as a smart drug loading platform for biomedical applications.