The development and application of nano-drug carriers might provide an excellent opportunity for cancer therapy. However, it is still an important challenge to realize the regulation and control of drug loading by analyzing the assembly process of carrier-loaded drugs. Herein, we show a “self-contained bioactive nanocarrier” system, which is prepared from ursolic acid, one of the very promising biologically active natural products with self-assembly properties. The study decrypts the assembly process of drug-carrier interaction and achieves the regulation of drug loading by controlling the interaction force. This nanocarrier highlights the unique advantages of active natural products in therapeutic efficacy and health benefits. In antitumor experiments, the carrier and drug demonstrated synergistic therapeutic efficacy. Furthermore, the nanocarrier is biosafe and capable of reducing the risk of liver damage induced by chemotherapeutics through the upregulation of key antioxidant pathways. Taken together, this “self-contained bioactive nanocarrier” system makes up for the drawback that conventional nanocarriers have no therapeutic efficacy and health benefits and eliminates the trouble of the toxic side effects associated with chemotherapy agents and the additional toxicity caused by long-term use of nanocarriers.

The application of natural small products with selfassembly characteristics in a drug-delivery system is attractive for biomedical applications because of its inherent biological safety and pharmacological activity, and there is no complex structural modification process. However, drug carriers with pharmacological effects have not been developed enough. Here, we report a pure natural nanomedicine-cum-carrier (NMC) drug delivery system. The NMC is formed by the direct co-assembly of two small molecular natural compounds through noncovalent interaction, and a molecular dynamics model for predicting the co-assembly of two small molecular compounds was established. The representative co-assembled NMC (oleanolic acid and glycyrrhetinic acid) not only shows excellent stability, high drug loading, and sustained release characteristics but also the co-assembled NMC formed by two small molecular compounds has a synergistic antitumor effect (CI < 0.7). After drug loading, the antitumor effect is further improved. In addition, this NMC highlights the unique advantages of active natural products in biosafety and health benefits. Compared with free drugs, it can reduce the liver damage caused by chemotherapy drugs through upregulating key antioxidant pathways. Compared to nonpharmacologically active drug delivery systems, it can reduce the risk of nanotoxicity. Taken together, this co-assembly drug-carrier system overcomes the shortcomings that pharmacologically active compounds cannot be directly applied, enhances the pharmacological activity of bioactive drug carriers, improves the antitumor efficacy, and slows down the side effects induced by chemotherapy drugs and the additional toxicity caused by long-term use of non-bioactive nanocarriers.

Self-assembling natural small molecules (NSMs) with favorable anticancer activity are of increasing interest as novel drug delivery platforms without structural modification for biomedical applications. However, a lack of knowledge and practicability of NSMs as drug carriers limited their current biomedical application. Here, via a green and facile supramolecular coassembly strategy, we report and develop a series of carrier-free terpenoid natural small moleculemediated coassembled photosensitive drugs for enhanced and synergistic chemo/photodynamic therapy. After screening 17 terpenoid NSMs, we identified 11 compounds that could form coassembled NSMs-Ce6 NPs with regulatable drug sizes. Analysis of the representative betulonic acid (BC)-mediated nano-coassemblies (BC-Ce6 NPs) reveals the high efficiency of the coassembly strategy and highlights the tremendous potential of NSMs as novel drug delivery platforms. Through molecular dynamics simulation and theoretical calculations, we elucidate the mystery of the coassembly process, indicating that the linear coplanar arrangement of BC dimeric units is primarily responsible for the formation of rod-like or spherical morphology. Meanwhile, we demonstrated that the reduced energy gap between the singlet and triplet excited states (ΔE ST ) facilitates efficient reactive oxygen species generation by promoting •OH generation via a type I photoreaction mechanism. The assembled nanodrugs exhibit multiple favorable therapeutic features, ensuring a remarkably enhanced, synergistic, and secure combinatorial anticancer efficacy of 93.6% with highly efficient tumor ablation. This work not only expands the possibility of natural biodegradable materials for wide biological applications but also provides a new perspective for the construction of NSM-mediated nano-coassemblies for precision therapy.

The supramolecular co-assembly properties of natural small molecules were revealed and carrier-free nano-drugs without structural modification were constructed.