Small molecule RNA-targeted photosensitizers for photodynamic therapy

Photodynamic therapy (PDT) is a minimally invasive cancer treatment modality with high spatial selectivity, whose therapeutic efficacy is largely governed by the photosensitizer's tissue penetration, singlet oxygen generation, and target specificity. In recent years, RNA has emerged as an attractive alternative target for PDT owing to its distinctive structural and biological features. In many cancers, ribosome biogenesis and nucleolar activity are markedly upregulated, leading to the accumulation of RNA species that are structurally exposed, highly abundant, and intrinsically susceptible to oxidative damage, thereby rendering RNA an efficient and accessible photodynamic target. RNA-targeted PDT enables selective photodamage without inducing permanent genomic lesions, reducing mutagenic risk while allowing light-triggered RNA degradation and precise spatiotemporal control of protein translation and cellular function. Moreover, unlike DNA damage, which can be partially repaired, oxidatively damaged RNA is typically eliminated through degradation rather than repair, enabling RNA-targeted PDT to circumvent repair-mediated resistance and achieve sustained cytotoxic effects. This Review summarizes recent advances in the molecular design of RNA-targeted photosensitizers, highlights their photophysical and biological mechanisms of action, and discusses the challenges and future opportunities for translating RNA-targeted PDT into clinical cancer therapy. • Recent advances in small-molecule RNA-targeted photosensitizers for photodynamic cancer therapy. • Structural design, binding mode, and photophysical properties of RNA-targeted photosensitizers. • RNA as a promising molecular target for precise PDT. • Advantages and mechanisms of RNA-targeted PDT strategies.