Enhancing the therapeutic effect of existing treatments or developing new non-invasive treatments are important measures to achieve high-efficiency treatment of malignant tumors. Photodynamic therapy (PDT) is an emerging treatment modality, and the key for achieving high-efficiency PDT is to select light with strong tissue penetration depth and enhance the generation of reactive oxygen species (ROS). Although the upconversion nanoparticles (UCNPs) modified with the photosensitizers could achieve PDT with strong penetration depth under near-infrared light irradiation, the ROS generated by traditional single-pathway PDT is still insufficient. Herein, we developed a novel nanoconjugate (UCNP-Ce6/AIEgen) for dual-pathway reinforced PDT, in which the UCNPs were co-modified with chlorin e6 (Ce6) and luminogen with aggregation-induced emission (AIEgen). Due to the presence of AIEgen, UCNP-Ce6/AIEgen could avoid aggregation-caused luminescence quenching in biological water environments and convert upconversion luminescence (UCL) of UCNPs to Ce6-activatable fluorescence. Therefore, under the irradiation of 808 nm laser, UCNP-Ce6/AIEgen can not only undergo direct lanthanide-triplet energy transfer to activate Ce6, but also convert the UCL of UCNPs to the light that can activate Ce6 through Fӧrster resonance energy transfer to generate more ROS, thus promoting tumor cell apoptosis. This work broadens the applications of nanoconjugates of lanthanide-based inorganic materials and organic dyes, and provides a conception for reinforced PDT of tumors.

Highly toxic reactive oxygen species (ROS) induced apoptosis and ferroptosis have been considered as significant cell death pathways for cancer therapy. However, insufficient amount of intracellular ROS extremely restricts the therapeutic effect. Toward this, we report a rationally designed nanocomposite (mUCC) with enhanced ROS generation ability, inducing the combination of apoptosis and ferroptosis through synergistic photodynamic therapy (PDT) and chemodynamic therapy (CDT). Under 808 nm near-infrared (NIR) light irradiation, photocatalytic reaction is triggered starting from the separation of electron–hole pairs on the surface of heterojunction (CeO₂/CuO), realizing improved ROS production. Simultaneously, mUCC served as Fenton-like agent exhibits considerable ability to generate highly toxic ·OH under tumor microenvironment (TME). The boosted accumulation of ROS disrupts the redox balance within tumor cells and results in the integration of apoptosis and ferroptosis. In addition, mUCC shows satisfactory tumor targeting property benefiting from the cancer cell membrane functionalization under the guidance of magnetic resonance imaging (MRI) and NIR fluorescence imaging. The intelligent mUCC with good biocompatibility and excellent antitumor response achieves efficient tumor elimination under synergistic PDT and CDT. This work offers an elective approach for further development of ROS-based therapeutic nanoplatform in cancer therapy.