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The potential toxicity of nanocarrier excipients and complicated preparation technologies have impeded the clinical application of nanomedicine. Recently, pure drug‐assembled nanosystems (PDANS) have been widely investigated, due to the unique self‐assembly characteristics of pure drug molecules. PDANS provides a facile nanoplatform for developing carrier‐free nanomedicine. Herein, the recent trends in PDANS for cancer therapy are outlined. First, the emerging strategies to develop single pure drug‐based nanoassemblies are discussed. Second, co‐assembly of two or more pure drugs for efficient combination therapy is overviewed. Then, the functional self‐assembly of non‐cytotoxic agents in tumor sites is presented. Finally, the rational design and self‐assembly mechanisms of these unique nanoplatforms are highlighted.

Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. In vivo, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.

Carrier-free prodrug-nanoassemblies have emerged as promising nanomedicines. In particular, the self-assembled nanoparticles (NPs) composed of homodimeric prodrugs with ultrahigh drug loading have attracted broad attention. However, most homodimeric prodrugs show poor self-assembly ability due to their symmetric structures. Herein, we developed photosensitizer-driven nanoassemblies of homodimeric prodrug for self-enhancing activation and chemo-photodynamic synergistic therapy. Methods: In this work, a pyropheophorbide a (PPa)-driven nanoassemblies of an oxidation-responsive cabazitaxel homodimer (CTX-S-CTX) was fabricated (pCTX-S-CTX/PPa NPs). The assembly mechanisms, aggregation-caused quenching (ACQ) effect alleviation, singlet oxygen generation, self-enhancing prodrug activation, cellular uptake, intracellular reactive oxygen species (ROS) generation and synergistic cytotoxicity of pCTX-S-CTX/PPa NPs were investigated in vitro . Moreover, the pharmacokinetics, ex vivo biodistribution and in vivo therapeutic efficacy of pCTX-S-CTX/PPa NPs were studied in mice bearing 4T1 tumor. Results: Interestingly, PPa was found to drive the assembly of CTX-S-CTX, which cannot self-assemble into stable NPs alone. Multiple intermolecular forces were found to be involved in the assembly process. Notably, the nanostructure was destroyed in the presence of endogenous ROS, significantly relieving the ACQ effect of PPa. In turn, ROS generated by PPa under laser irradiation together with the endogenous ROS synergistically promoted prodrug activation. As expected, the nanoassemblies demonstrated potent antitumor activity in a 4T1 breast cancer BALB/c mice xenograft model. Conclusion: Our findings offer a simple strategy to facilitate the assembly of homodimeric prodrugs and provide an efficient nanoplatform for chemo-photodynamic therapy.