NIR-triggered upconversion nanoreactor for combined photodynamic therapy and cancer immunotherapy

Lanthanide-doped upconversion nanoparticles (UCNPs) have revolutionized theranostics nanoplatforms owing to their excellent photostability, high tissue penetration depth, relatively low toxicity, and negligible autofluorescence. By converting near-infrared (NIR) excitation into ultraviolet or visible emissions, UCNPs can remotely activate photosensitizers (PSs) or photocatalytic components, thereby enabling photodynamic therapy (PDT) in deeper tissues. However, PDT alone often exhibits limited therapeutic efficacy because of tumor hypoxia, restricted ROS diffusion, heterogeneous PS distribution, and the immunosuppressive tumor microenvironment (TME). Therefore, PDT has increasingly been combined with complementary therapeutic strategies to enhance tumor destruction and overcome therapeutic resistance. Among these approaches, cancer immunotherapy has attracted considerable attention because PDT-induced oxidative stress can promote immunogenic cell death (ICD), leading to the release of tumor-associated antigens and damage-associated molecular patterns. These immunogenic signals can promote cytotoxic T lymphocytes and elicit systemic antitumor immune responses, thereby potentially suppressing tumor recurrence and metastasis.
In this study, we developed an 808 nm NIR-excitable UCNP-based nanoreactor incorporating a TME-responsive catalytic component for combined PDT and cancer immunotherapy. Upon 808 nm NIR irradiation, the upconversion emission generated by the UCNPs activates the photosensitizing or photocatalytic sites, leading to the production of highly cytotoxic ROS and subsequent oxidative damage to tumor cells. In addition, folate-functionalized polyethylene glycol-based block copolymer was introduced to improve colloidal stability, biocompatibility, and tumor-targeting ability of the nanoreactor. The physicochemical properties, NIR-triggered ROS generation, ICD induction, and immune activation of the nanoreactor were systematically evaluated.