A photoimmune synergizing RNA interference technology for highly effective antitumor treatment.

Photoimmunotherapy and RNA interference (RNAi) hold great potential for tumor therapy but exhibit limited efficacy as monotherapies. In this work, we report a red-light-activated combinatorial therapy that integrates photodynamic immunotherapy (PIT) with RNAi via a rationally designed photosensitizer, FNBS, developed on the basis of our previously reported advanced photosensitizer platform, HNBS. Upon cellular uptake and following red light irradiation, FNBS induces pyroptosis through the activation of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 inflammasome pathways, thereby enhancing antitumor immune responses and converting "cold" tumors into "hot" tumors. Meanwhile, ROS-mediated oxidation of the furan moiety enables covalent RNA crosslinking and subsequent RNA degradation, thereby facilitating targeted RNAi. Owing to this dual mechanism, effective cancer cell elimination is achieved under normoxic (21% O2) and hypoxic (2% O2) conditions. FNBS has an IC50 as low as 80 nM. In addition, RNA sequencing analysis reveals that FNBS-induced cell death is closely associated with RNA-related pathways, including RNA metabolism and RNA degradation. Collectively, this work establishes a novel combinatorial therapy strategy in which photodynamic therapy, immunotherapy, and RNA interference are integrated within a single small-molecule platform, providing a foundation for achieving more effective cancer treatment.