Natural products have always been a treasure trove for clinical drug development and a source of inspiration for lead compounds in the process of new drug discovery. However, two-dimensional cell cultures and animal models in the traditional drug development model have serious limitations in generalizing human physiopathology and cannot accurately predict the real clinical response of the human body to drugs, which brings obstacles and challenges to drug evaluation. Organ-on-a-chip (OoC) is an emerging technology based on microfluidic platforms and in vitro cell culture that can mimic the physiological environment and function of human organs for disease modeling and drug evaluation. In this review, we explore several major examples of how human single-OoC systems can be used to simulate complex disease models and outline recent advances in organoids for natural drug screening. Finally, we summarize the challenges and future trends that OoCs must overcome in drug discovery and development. Overall, this review highlights that OoCs, instead of animal models, open new avenues for natural drug development and evaluation, therapeutic innovation, and in vivo embodiment of personalized medicine.

Natural plant compounds have long served as crucial sources of medicinal therapies, spanning millennia and underpinning the field of drug discovery and development. Their profound impact is rooted in their extensive diversity and broad spectrum of pharmacological activities. Inspired by the decoction methods of traditional Chinese medicine, we have delved into the co-assembly strategy of natural plant compounds. This strategy involves the coalescence of active components from various drugs into nanocomplexes via non-covalent interactions during the decoction process. Consequently, this approach enhances the biocompatibility, biodegradability, and pharmacological efficacy of natural plant small molecules while mitigating their toxicity. The co-assembly strategy capitalizes on the inherent advantages of natural plant compounds, thereby expediting drug discovery by repurposing existing drugs. This review outlines the evolution of co-assembly strategies involving natural plant compounds, provides illustrative examples of co-assembly, elucidates the mechanisms underlying assembly, and highlights the resultant advantages. By shedding light on the transition from single molecule to multi-component interactions, this review advances our understanding, facilitating further research and the practical application of co-assembly strategies for natural plant compounds.