Cancer cells in hypoxic tumors are remarkably resistant to photodynamic therapy. Here, we hypothesize that an oxygen and Pt(II) self-generating multifunctional nanocomposite could reverse the hypoxia-triggered PDT resistance. The nanocomposite contains Pt(IV) and chlorin e6, in which upconversion nanoparticles are loaded to convert 980 nm near-infrared light into 365 nm and 660 nm emissions. Upon accumulation at the tumor site, a 980 nm laser is used to trigger the nanocomposite to generate O₂ for consumption in the PDT process and to produce cytotoxic reactive oxygen species. The composite also releases active Pt(II) for synergistic photo-chemo therapy to enhance antitumor efficiency. The oxygen and Pt(II) self-generating prodrug is shown to have high potential to inhibit tumors out of the range of UV light, to overcome the hypoxia-triggered PDT resistance and significantly improve anticancer efficacy by the synergistic PDT-chemotherapy.

Triple-negative breast cancer (TNBC) is the most metastatic and recurrent subtype of all breast cancers. Owing to the lack of therapeutic targets, chemotherapy and surgical intervention are the only treatments for TNBC. However, the effectiveness of chemotherapeutics is limited by its shortcomings such as poor targeting, easy removal and high toxicity. Recently, exosomes have attracted more and more attention as a drug delivery system. As endogenous vesicles, exosomes ensure low immunogenicity, nontoxicity, and long blood circulation time. In addition, immune cell-derived exosomes can mimic the immune cell to target tumor cells. Herein, we developed a macrophage-derived exosome-coated poly(lactic-co-glycolic acid) nanoplatform for targeted chemotherapy of TNBC. To further improve the tumor targetability, the surface of the exosome was modified with a peptide to target the mesenchymal–epithelial transition factor (c-Met), which is overexpressed by TNBC cells. The results showed that the engineered exosome-coated nanoparticles significantly improved the cellular uptake efficiency and the antitumor efficacy of doxorubicin. In vivo study demonstrated that the nanocarriers exhibited remarkable tumor-targeting efficacy, led to increased inhibition of tumor growth and induced intense tumor apoptosis. These results indicated that the engineered macrophage exosome-coated nanoparticles were a promising drug delivery strategy for TNBC treatment.

Packaging multiple drugs into a nanocarrier with rational design to achieve synergistic cancer therapy remains a challenge due to the intrinsically varied pharmacodynamics of therapeutic agents. Especially difficult is combining small-molecule drugs and macromolecular biologics. Here, we successfully graft pheophorbide A (PPA) photosensitizers on DNA backbone at predesigned phosphorothioate modification sites. The synthesized four PPA-grafted DNAs are assembled into a tetrahedron framework, which further associates with a programmed death ligand-1 (PD-L1) small interfering RNA (siRNA) linker through supramolecular self-assembly to form an siRNA and PPA copackaged nanogel. With dual therapeutic agents inside, the nanogel can photodynamically kill tumor cells and induce remarkable immunogenic cell death. Also, it simultaneously silences the PD-L1 expression of the tumor cells, which substantially promotes the antitumor immune response and leads to an enhanced antitumor efficacy in a synergistic fashion.