PD‐L1 Aptamer‐Functionalized Metal–Organic Framework Nanoparticles for Robust Photo‐Immunotherapy against Cancer with Enhanced Safety

Immune checkpoint blockade has become a paradigm‐shifting treatment modality to combat cancer, while conventional administration of immune checkpoint inhibitors, such as anti‐PD‐L1 antibody (α‐PD‐L1), often shows unsatisfactory immune responses and lead to severe immune‐related adverse effects (irAEs). Herein, we develop a PD‐L1 aptamer‐based spherical nucleic acids (SNAs), which consists of oxaliplatin (OXA) encapsulated in a metal–organic framework nanoparticle core and a dense shell of aptPD‐L1 (denoted as M@O‐A). Upon light irradiation, this nanosystem enables concurrent photodynamic therapy (PDT), chemotherapy, and enhanced immunotherapy in one shot to inhibit both primary colorectal tumors and untreated distant tumors in mice. Notably, M@O‐A shows scarcely any systemic immunotoxicity in a clinical irAEs‐mimic transgenic mouse model. Collectively, this study presents a novel strategy for priming robust photo‐immunotherapy against cancer with enhanced safety. PD‐L1 aptamer‐functionalized metal–organic framework (M@O‐A) nanoparticles for synergetic cancer chemotherapy, PDT, and immune checkpoint blockade with reduced immunotoxicity are reported. M@O‐A selectively targets and blocks the highly PD‐L1‐expressing tumor cells and decomposes under laser irradiation to release reactive oxygen species (ROS) and oxaliplatin (OXA), eliciting immunogenic cell death (ICD) and therefore an enhanced immunotherapy and simultaneously attenuated irAEs.