Self-assembled lipid–prodrug nanoparticles

Nanomedicines suffer from poor drug loading and uncontrolled ‘burst release’ after administration. Combining prodrug strategies with nanostructured carriers can help to overcome these limitations by improving diffusion through biological barriers, enzymatic activation of the lipid conjugate in the diseased area, drug protection, pharmacokinetics and biodistribution, intracellular delivery and/or targeting properties. Owing to fundamental advances in supramolecular chemistry and the fine-tuning of drug, lipid and drug–lipid chemical link modifications, it is now possible to develop lipid–prodrug conjugates that can spontaneously self-assemble into nanoparticles in aqueous media with unique supramolecular organizations and without additional excipients. In this Review, we describe the chemical synthesis, physicochemical properties, structure and pharmacological activity of lipid–prodrug-based nanomedicines and discuss the path towards clinical translation for the treatment of severe diseases. Combining the benefits of nanoparticle carriers and prodrugs can improve drug delivery efficiency. This Review discusses the design of lipid–prodrug nanomedicines with self-assembly properties for modulating drug release, reducing drug metabolism, and improving the pharmacokinetics and biodistribution for the treatment of severe diseases.