Nanocrystalline Drug Delivery Systems for Natural Compounds: Progress, Challenges and Future Opportunities

Herbal medicines, under the guidance of Traditional Chinese medicine (TCM) theory, have played an irreplaceable role in treating and controlling various diseases for centuries. However, both traditional and contemporary TCM formulations are plagued by drawbacks such as complex preparation processes, poor stability, and the inconvenience of water decoction. Moreover, natural active ingredients derived from TCM, despite their definite physicochemical properties and significant therapeutic potential-exemplified by the anticancer effects of terpenoids like paclitaxel and tretinoin, and the antihypertensive properties of flavonoids including artemisinin and quercetin-face substantial hurdles in clinical translation due to poor aqueous solubility, low bioavailability, and potential toxicity. Nanocrystalline drug delivery systems (NCDDS) have emerged as a versatile strategy to address these limitations, leveraging the unique properties of nanocrystals to enhance drug dissolution, improve bioavailability, and enable targeted delivery. This review synthesizes recent advancements in NCDDS for natural compounds, elaborating on the current cutting-edge status of preparation techniques and characterization methods, as well as key progress in enhancing the in vitro and in vivo efficacy of natural agents, including terpenoids, flavonoids, and polyphenols. Despite these accomplishments, several challenges persist, such as inadequate colloidal stability, obstacles in scaling up production, and potential long-term toxicity concerns. Future opportunities are centered on the development of advanced nanocrystal preparation technologies, integration with multifunctional modification techniques, and exploration of interdisciplinary cross-applications. The objective of this review is to offer insights into the current landscape of NCDDS for natural compounds and to guide further research efforts toward addressing existing challenges, thereby expediting their clinical translation.