Mechanistic Design of a Rotor-HOMO coupled AIEgen Integrated with DDR2 Inhibition for Triple-Action Phototheranostic Eradication of Metastatic Tumors

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Metastatic tumor eradication demands therapeutic strategies that overcome both cellular and microenvironmental drivers of invasion. Here we report a triple-action phototheranostic nanoplatform that integrates a mechanistically optimized aggregation-induced emission luminogen (AIEgen) with targeted stromal modulation. A new design rule “Rotor–HOMO electronic coupling” was employed to develop a donor–acceptor AIE molecule (TQ-4TPE) with high photothermal conversion performance. This design involves the strategic placement of molecular rotors at positions that ensure their electronic coupling with the chromophore's Highest Occupied Molecular Orbital (HOMO). Through a systematic isomeric study, we demonstrate that this Rotor-HOMO coupling promotes large-amplitude torsional relaxation and a high reorganization energy that funnels excited-state energy into heat. To target the fibrotic tumor microenvironment, TQ-4TPE is co-encapsulated with WRG-28, a selective allosteric inhibitor of the collagen receptor DDR2, and cloaked in cancer cell membranes to yield biomimetic stealth nanoparticles (4T/W@MPs). Upon NIR laser activation, this single agent induces acute tumor ablation while simultaneously suppressing cancer-associated fibroblasts (CAFs) and collagen deposition. In syngeneic breast cancer models, the platform achieves near-complete primary tumor regression with minimal off-target damage and abrogates metastasis in a CAF-rich co-implantation model. The synergy of mechanistic photothermal enhancement, precise image-guided ablation, and pro-active stromal remodeling offers a novel paradigm for metastasis-directed therapy.

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