Molecular Engineering-Driven Self-Assembled Nanotheranostic System for Mannose-Targeted Synergistically Enhanced Photothermal-Photodynamic Precision Therapy in Colorectal Cancer

Cyanine dyes (Cy) possess excellent properties for biomedical applications, but their effectiveness is hampered by disordered aqueous aggregation and photophysical instability. To address these challenges, we rationally engineer the heptamethine cyanine (Cy7) scaffold by integrating tetraphenylethylene (TPE)─a rigid π-conjugated hydrophobic moiety─and tumor-targeting mannose, a hydrophilic glycan that recognizes overexpressed mannose receptors (MR) on cancer cells. This molecular design enables spontaneous self-assembly, driven by hydrophilic-hydrophobic interactions, into well-defined, carrier-free nanoparticles (TCM NPs). TCM NPs serve as an immunogenically safe, multifunctional nanoplatform that integrates MR-targeted delivery, near-infrared (NIR) imaging, and dual phototherapy. Mechanistically, the twisted conformation of TPE introduces steric hindrance, effectively suppressing intramolecular π-π stacking and fluorescence quenching while enhancing nonradiative decay, resulting in a remarkable 58.6% photothermal conversion efficiency. Simultaneously, the excited state of TCM facilitates efficient S₁ → T₁/T₂ transitions and intersystem crossing (ISC), thereby amplifying reactive oxygen species (ROS) generation to synergistically drive both photothermal therapy (PTT) and photodynamic therapy (PDT). Both in vitro and in vivo evaluations confirm potent antitumor efficacy: TCM NPs mediate approximately 91.0% killing of MR⁺ tumor cells in vitro and achieve 96.5% tumor growth inhibition in vivo. Overall, by synergistically integrating glycotargeting and structural distortion, Cy7 is reprogrammed into a highly effective, carrier-free, theranostic agent. This work provides a foundation for the rational modulation of Cy photophysics and active targeting, advancing the development of a Cy-based precision cancer nanomedicine.