Supramolecular gels based on natural small molecules: Building the bridge between natural products and future creative medicine

Natural small molecules (NSMs) sourced from traditional Chinese medicine (TCM) have played an indispensable and significant role in developing new drugs and clinical applications. However, many of them face obstacles due to their insufficient specificity, low bioavailability, and serious side effects. Over the past few decades, supramolecular gels formed by natural small molecules (NSMs-SGs) have been widely investigated with outstanding advantages, such as excellent sustained-release performance, various methods of delivery, better therapeutic effects, and simple preparation techniques, demonstrating great potential in the fields of materials science and TCM chemistry. In this article, the current research status and trends of NSMs-SGs rooted in TCM are meticulously outlined, the classifications, structures, and corresponding self-assembly mechanisms of different types of NSMs-SGs are discussed in detail, and the functional properties of NSMs-SGs inheriting from TCM are summarized. It is particularly noteworthy that this article focuses on the interesting physical-chemical or pharmacokinetic changes that supramolecular gels impart to NSMs. These changes promote the efficacy of NSMs and reduce their toxicity. For instance, glycyrrhizic acid (GA), a typical compound with a long-standing application history in TCM, is specifically illustrated as a representative. By analyzing all of these, we aim to provide theoretical insights and references for future in-depth studies and designs of NSM assemblies, with the ultimate goal of further unlocking the mysteries of TCM-derived NSMs in modern pharmaceutical research.