Tumor Microenvironment-Triggered Nanocrystal-to-Nanocrystal Transformation for RNA-Boosted Photo-STING Therapy

Photosensitizers in nanocrystals have emerged as promising avenues for immune stimulation through enhanced reactive oxygen species (ROS) generation relative to their amorphous structures. However, their rigid molecular packing severely restricts the molecular variations necessary for stimuli-responsive conversion in the crystalline state, resulting in challenges for these nanocrystals to undergo dynamic and on-demand immune regulation, particularly under the tumor microenvironment (TME) stimulation. Herein, we address this challenge by developing 2TZP, a photosensitizer engineered with a synergistic proton-capturing motif that confers a narrow pH response range within the TME. This design enables a specific and complete acid-triggered nanocrystal-to-nanocrystal (NCNC) transformation, from hexagonal prism to cuboid prism, directly activated by TME (pH 6.5) with a narrow response range of 0.70 pH units. This process involves significant conformational distortion, subtle rotation, and slippage within the preserved crystalline lattice, which is favored by sensitive responsiveness, sufficient free volume, and crystal lattice similarity before and after nanocrystal transformation. Crucially, this mechanism serves a dual purpose. It intensifies the twisted intramolecular charge transfer (TICT) effect, boosting intersystem crossing (ISC), while simultaneously unveiling latent RNA binding to form an electron reservoir pump and thereby enhancing ROS generation. Thus, the transformed 2TZP nanocrystals further potentiate their ability to target the nucleolus, causing oxidative damage to the nucleolus and leading to pronounced nuclear disruption and enhanced dsDNA leakage. This then effectively ensures potent, on-demand activation of the cGAS-STING immune pathway while concurrently inducing robust immunogenic cell death (ICD) under an acidic TME. This work not only demonstrates a model of NCNC transformation within the TME, but also establishes a design principle to couple structural regulation with dynamic, on-demand function amplification for potential photoimmunotherapy.