Recent advances in carrier-free natural small molecule self-assembly for drug delivery.

Natural small-molecule drugs have been used for thousands of years for the prevention and treatment of human diseases. Most of the natural products available on the market have been modified into various polymer materials for improving the solubility, stability, and targeted delivery of drugs. However, these nanomedicines formed based on polymer carriers would produce severe problems such as systemic toxicity and kidney metabolic stress. In contrast, the carrier-free nanomedicines formed by their self-assembly in water have inherent advantages such as low toxicity, good biocompatibility, and biodegradability. This review summarizes the assembly process and application of natural small-molecule products, which are mainly driven by multiple non-covalent interactions, and includes single-molecule assembly, bimolecular assembly, drug-modified assembly, and organogels. Meanwhile, the molecular mechanism involved in different self-assembly processes is also discussed. Self-assembly simulation and structural modification of natural small-molecule products or traditional Chinese medicine molecules using molecular dynamics simulation and computer-assisted methods are proposed, which will lead to the discovery of more carrier-free nanomedicine drug delivery systems. Overall, this review provides an important understanding and strategy to study single-molecule and multi-molecule carrier-free nanomedicines.