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This study introduces a novel approach for synthesizing Benzoxazine‐centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous signal molecule with multiple physiological functions, and it also plays a key role in cancer therapy. However, the production of NO which depends on O2 or H2O2 is limited within the tumor microenvironment, leading to unsatisfactory anticancer effect. Herein, we report a NO‐based phototherapeutic strategy mediated by photogenerated holes for hypoxic tumors, which is achieved by irradiation of the poly‐L‐arginine modified carbon‐dots‐doped graphitic carbon nitride nanomaterial (ArgCCN). Upon red light irradiation, the photogenerated holes on ArgCCN oxidized water into H2O2 which subsequently oxidized the arginine residues to produce NO. In vitro and in vivo experiments showed that the high concentration of NO produced by ArgCCN could induce cancer cell apoptosis. The presented phototherapeutic strategy is based on microenvironment‐independent photogenerated holes mediated oxidation reaction, paving the way for the development of NO therapeutic strategy. [ABSTRACT FROM AUTHOR]