Photo‐Generated ¹ O ₂ Triggers In Situ RNA Crosslinking for High‐Contrast Tumor MRI and Effective Tumor Suppression

Abstract

ABSTRACT High‐contrast imaging and effective treatment of hepatocellular carcinoma (HCC) remain challenging, largely due to the limited tumor selectivity of existing contrast agents and the absence of stable and broadly conserved therapeutic targets. Herein, we report a photoactivatable molecular magnetic resonance/fluorescence (MR/FL) imaging probe for sensitive HCC imaging and potent tumor eradication that exploits the intrinsically RNA‐enriched nature of HCC. Upon light irradiation, singlet oxygen ( 1 O 2 ) triggers in situ furan–RNA crosslinking, prolonging its rotational correlation time ( τ r ), thereby markedly amplifying r 1 relaxivity. Notably, this light‐activated furan–RNA crosslinking strategy affords a 75% enhancement in tumor MR signal, significantly outperforming clinically used MR contrast agents. FL imaging further reveals prolonged tumor retention with detectable signals persisting for over 14 days, highlighting its potential for longitudinal monitoring of therapeutic response. Concurrently, photo‐generated 1 O 2 and following RNA crosslinking results in multiple cell death mechanism, including pyroptosis, ferroptosis and RNA interference, enabling sustained tumor suppression. This work presents the first photoactivatable RNA‐targeted MR/FL imaging probe and establishes a new paradigm that integrates molecular‐level MRI signal amplification, long‐term tumor retention, and multi‐pathway synergistic antitumor therapy for holistic HCC management.