Functional matrix engineering enables aggregate-state photophysics in tumor-responsive organic NIR-II phototheranostics.

Organic NIR-II phototheranostic nanoparticles function as molecular assemblies, making their optical performance fundamentally dependent on aggregate-state photophysics governed by intermolecular organization. However, exploiting the matrix to actively program intermolecular organization during nanoparticle assembly remains largely unexplored. Here, we establish functional matrix engineering as a practical implementation of assembly engineering, in which tumor-microenvironment-responsive prodrugs serve as multifunctional matrix components that reorganize intermolecular packing to enhance aggregate-state photophysics while simultaneously enabling therapeutic activation. A benzobisthiadiazole (BBT)-based D-A-A-D fluorophore (2A895) was co-assembled with two tumor-microenvironment-responsive prodrugs (CPB and Dyl) serving as multifunctional matrix components. Molecular dynamics simulations reveal that the functional matrix reorganizes intermolecular packing by disrupting compact π-π contacts, and indicates reduced electronic coupling through enlarged centroid separation and non-parallel packing, thereby suppressing aggregation-caused quenching and enhancing NIR-II fluorescence without compromising photothermal conversion. Meanwhile, the stimulus-responsive matrix enables H2O2-triggered chlorambucil release and concomitant GSH depletion, amplifying oxidative stress to potentiate chemo-photothermal therapy. The resulting nanoparticles exhibit enhanced NIR-II fluorescence and photoacoustic imaging together with robust in vivo antitumor efficacy. Overall, functional matrix engineering provides a general strategy for regulating molecular assemblies through matrix design rather than fluorophore redesign.