Abstract

Precise and controllable RNA editing presents a powerful therapeutic strategy for oncogene silencing in cancer treatment. Here, we introduce a photothermal-activatable host-guest supramolecular delivery system enabling spatiotemporally regulated expression of CasRx, a compact RNA-guided RNA endonuclease, for targeted survivin mRNA knockdown in hepatocellular carcinoma. The modular platform is constructed through dynamic assembly of β-cyclodextrin-conjugated polydisulfide and adamantane-functionalized conjugated small molecules through host-guest interactions, enabling the integration of photothermal agents into the delivery vectors that can encapsulate the heat-inducible expression of plasmid encoding CasRx. Upon the near-infrared (NIR) laser irradiation, the moieties containing conjugated small molecules can convert light to heat so as to trigger the specific expression of CasRx in tumor tissue, leading to efficient and selective degradation of survivin transcripts. This supramolecular platform integrates the photothermal switch and delivery carriers and precisely controls RNA editing in vivo, avoiding potential systemic toxicity induced by off-target delivery. Our study establishes a programmable and precise RNA regulation platform in vivo by means of supramolecular assembly for safe, tunable, and effective RNA-based cancer therapy.