Enhanced Upconversion Luminescent Nanocarrier for Effective Tumor‐Targeted Photodynamic Therapy Combined with Immunotherapy

ABSTRACT Combination cancer therapy, a treatment modality combining two or more therapeutic strategies, has attracted attention for treating various types of cancer. In this study, we produced near‐infrared (NIR)‐induced multi‐shell upconversion nanoparticle (MUN)‐based therapeutic nanocarriers co‐loaded with chlorin e6 (Ce6) and indoximod (IND) (FMUN3‐Ce6/IND) to combine tumor‐targeted photodynamic therapy (PDT) with immunotherapy. Upconversion nanoparticles doped with rare‐earth elements are synthesized into multi‐shell structures to improve their upconversion luminescence efficiency. In particular, their emission intensity in the red region, which is the excitation wavelength of Ce6, increased by ∼519 times compared with the core nanoparticles, which enhanced the PDT effect. The MUN‐based nanocarriers showed more than 18‐fold better ROS generation than free Ce6 under 808 nm NIR laser irradiation. FMUN3‐Ce6/IND nanocarriers conjugated with a folic acid ligand showed particularly high phototoxicity to HeLa cells overexpressing folate receptors due to their active targeting effect. FMUN3‐Ce6/IND nanocarriers increased the ratio of CD3 + CD8 + to CD3 + CD4 + FoxP3 + T cells by approximately 5.4‐fold compared to FMUN3‐Ce6 without IND, indicating that inhibition of Trp metabolism by IND effectively promotes CD8 + T cell proliferation and suppresses Treg cells, thereby enhancing the antitumor immune response. Furthermore, the synergistic antitumor efficacy of FMUN3‐Ce6/IND combining PDT and immunotherapy under in vivo conditions is demonstrated. These results suggest that multi‐shell FMUN‐based nanocarriers offer a promising platform for synergistic combination therapy, addressing the limitations of monotherapy with IDO inhibitors and overcoming the restricted tissue penetration and low ROS generation associated with conventional PDT.