The antitumor efficiency and clinical translation of traditional nanomedicines is mainly restricted by low drug loading, complex preparation technology, and potential toxicity caused by the overused carrier materials. In recent decades, small‐molecule prodrug nanoassemblies (SMP‐NAs), which are formed by the self‐assembly of prodrugs themselves, have been widely investigated with distinct advantages of ultrahigh drug‐loading and negligible excipients‐trigged adverse reaction. Benefited from the simple preparation process, SMP‐NAs are widely used for chemotherapy, phototherapy, immunotherapy, and tumor diagnosis. In addition, combination therapy based on the accurate co‐delivery behavior of SMP‐NAs can effectively address the challenges of tumor heterogeneity and multidrug resistance. Recent trends in SMP‐NAs are outlined, and the corresponding self‐assembly mechanisms are discussed in detail. Besides, the smart stimuli‐responsive SMP‐NAs and the combination therapy based on SMP‐NAs are summarized, with special emphasis on the structure–function relationships. Finally, the outlooks and potential challenges of SMP‐NAs in cancer therapy are highlighted.

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

Prodrug-nanoparticles turn the disadvantage of the aggregation-caused quenching effect into an advantage to promote dual-modality PR104A release. Besides, photodynamic therapy-induced hypoxia activates PR104A for high-efficiency synergistic therapy.

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