Polyphenol functional self-assembled drug delivery systems: Mechanism, application, and future intelligent precision assembly mode

Polyphenolic compounds can serve not only as therapeutic drugs but also as carriers for self-assembled delivery systems, offering significant advantages for self-assembled drug delivery systems. Recently, a systematic review by Professor Zhang Dingkun's research group has provided breakthrough insights into this field. The paper systematically analyzed the interaction mechanism between polyphenols and drug molecules, highlighting the outstanding advantages of polyphenol-based self-assembled complexes in enhancing therapeutic efficacy, achieving targeted drug delivery, and overcoming biological barriers. At the same time, it proposed future research, development, and application strategies for polyphenol self-assembled drug delivery systems (PSA) in terms of intelligent characterization, intelligent assembly, and intelligent delivery, to address current challenges in PSA.

Natural polyphenols not only possess therapeutic effects including antioxidant, anti-inflammatory, and anti-tumor activities, but also can self-assemble with metal ions, proteins, and polymers via non-covalent interactions such as hydrogen bonding, hydrophobic interactions, and metal coordination to form functionalized nanocomposites. Compared to conventional covalent carriers, polyphenol self-assembly systems have unique advantages, such as intelligent targeting (enabling precise controlled release via pH-, enzyme-, and reduction-responsive mechanisms), functional integration (dual roles of therapeutic effect and carrier to enhance stability and efficacy), and biocompatibility, providing efficient and safe solutions for drug delivery. The research team demonstrated its clinical potential through representative case studies: in tumor treatment, DOX@BSA-TP-FANS nanospheres, through the synergistic effect of folic acid-targeted recognition and enzyme-responsive controlled release, increased the apoptosis rate of tumor cells by three times; the BA-peptide nanofiber system for myocardial injury repair achieved an eightfold drug enrichment at the injury site and simultaneously exerted antioxidant and ferroptosis inhibition functions; and the QCS/TA hydrogel successfully regulated the complex pathological microenvironment through reactive oxygen species scavenging, broad-spectrum antibacterial activity, and self-healing properties. Particularly noteworthy is the tannic acid-Fe³⁺ microporous coating technology. This "armored probiotic" system achieved a reduction of over 90% in local antibiotic concentration through selective adsorption, achieving a breakthrough in probiotic activity protection. It has now been granted patents in both China and the United States and has entered Phase I clinical trials for inflammatory bowel disease.

However, this field still faces challenges such as size heterogeneity caused by non-covalent assembly, quality instability due to fluctuations in production parameters, and low R&D efficiency due to conventional trial-and-error approaches. To overcome these challenges, the team proposed a "molecular design – simulation optimization – intelligent production – virtual validation" R&D framework. This framework integrates multi-scale modeling and deep learning to screen stable complexes, combines 3D printing, microfluidics, and machine learning to achieve precise assembly and quality control, and fuses in vitro dissolution data with physiologically based pharmacokinetic (PBPK) models to predict the balance between efficacy and safety. Despite the challenges in stability and scalable production, the integration of the intelligent manufacturing framework with Pharma 4.0 technologies is expected to overcome the limitations of traditional processes and advance the development of self-assembled drug delivery systems.

This research was supported by the National Natural Science Foundation of China (82304871, 81973493), the Natural Science Foundation of Sichuan Province (2024NSFSC1846), and the Innovation Team Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202209).

About the Authors

The First Author: Feng Jiamin, female, is a master's student at the School of Pharmacy, Chengdu University of Traditional Chinese Medicine. Her research focuses on new technologies, novel dosage forms, and processing of traditional Chinese medicine (TCM) preparations. She has published two papers as an author in Carbohydrate Polymers and Chinese Journal of Traditional Chinese Medicine.

Co-First Author: Wei Xiaorong, female, is a master's student at the School of Pharmacy, Chengdu University of Traditional Chinese Medicine. Her research focuses on new technologies, novel dosage forms, and processing of TCM preparations. She has published two academic papers as first or co-first author.

Corresponding Author: Zhang Dingkun, male, is a professor and doctoral supervisor at Chengdu University of Traditional Chinese Medicine. He is a Young Top-Notch Talent of the National Ten Thousand Talents Program and a Tianfu Science and Technology Elite under Sichuan Province’s Tianfu Qingcheng Program. His work focuses on TCM new drug development, green manufacturing, and intelligent manufacturing. He serves as an editorial board member of Pharmacological Research and a young editorial board member for journals including Chinese Herbal Medicine, Chinese Journal of Experimental Prescriptions, World Journal of Traditional Chinese Medicine, and China Journal of Pharmaceutical Industry. He is also a standing committee member of the Chinese Medicine Pharmaceutical Engineering Branch of the China Association of Chinese Medicine, a member of its Youth Committee and Chinese Medicine Preparation Branch, and a member of the Clinical Chinese Medicine Branch of the Chinese Pharmaceutical Association. He has presided over three projects funded by the National Natural Science Foundation of China, the Sichuan Province Outstanding Youth Project, and the Sichuan Province Major Science and Technology Special Project. As the primary researcher, he participated in a national major science and technology special project. He has undertaken over 10 enterprise-commissioned projects and completed technological upgrades for multiple Chinese patent medicines, including products for Sinopharm Taiji, China Resources Sanjiu, and Yipinhong Pharmaceutical. As first or corresponding author, he has published over 80 SCI papers (including 3 ESI highly cited papers) in journals such as Carbohydrate Polymers、ACS Applied Materials & Interfaces、Food Research International. He is ranked among the world’s top 2% of scientists and holds 26 authorized invention patents.

Huang Haozhou, male, holds a Doctor of Traditional Chinese Medicine degree and a postdoctoral degree in TCM from Chengdu University of Traditional Chinese Medicine. He is an associate researcher and master’s supervisor. He serves as a director of the Intelligent Decision-Making Branch for Comprehensive Evaluation of TCM at the China Association of Chinese Medicine Information, a young editorial board member of Food & Medicine Homology, a guest editor of JOVE, and a reviewer for journals including Frontiers in Pharmacology. His research focuses on novel preparations, dosage forms, and applications of TCM and ethnic medicine. He has presided over eight projects, including the National Natural Science Foundation of China for Young Scientists, the China Postdoctoral Science Foundation, and the Natural Science Foundation of Sichuan Province. As a key member, he has participated in over ten projects, including the National Natural Science Foundation of China Regional Joint Fund, the Ministry of Science and Technology’s Key Special Project "Modernization of Traditional Chinese Medicine," and the Sichuan Province Major Science and Technology Special Project. As first or corresponding author, he has published over 40 academic papers in journals such as Carbohydrate Polymers、ACS Applied Materials & Interfaces、Food Research International. He holds five national invention patents and has co-edited four monographs.

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.