An Intermediate-Centric View of Cascade Cancer Nanotherapeutics

Cascade therapies have emerged as a paradigm-shifting strategy against cancer, exploiting consecutive, self-amplifying biochemical reactions to convert endogenous or externally supplied substrates into potent cytotoxic species. The marriage of this principle with nanotechnology has birthed "cascade nanotherapeutics", which has proved augmented anticancer efficacy through integrating temporally coordinated catalytic, photonic, and redox activities within nanoscopic dimensions. In this review, we survey the most recent literature on cascade nanosystems for cancer therapy, proposing an intermediate-centric view based on the pivotal small-molecules or physicochemical signals that drive the antitumor cascades. These key intermediates include: (i) H₂O₂, (ii) O₂, (iii) singlet oxygen (¹O₂), (iv) glutathione (GSH), and (v) localized hyperthermia, (vi) pH, and (vii) NO. For each category, we systematically discuss design principles and mechanistic underpinnings to establish fundamental structure-activity relationships from a cascading perspective. Finally, we address unresolved challenges and outline future research outlook for next-generation cascade nanotherapeutics with simple composition, adaptive intelligence, potent efficacy and clinical-grade biosafety.