Nonconjugated Side-Chain Engineering Enables Through-Space Interactions for Stimuli-Responsive Photodynamic Therapy

Efficient and stimulus-modulated intersystem crossing (ISC) in photodynamic therapy (PDT) is usually designed via molecular engineering of π-conjugated core structures. Herein, we report that nonconjugated protonatable imide side chains of perylene diimide (PDI) photosensitizers can function as through-space electrostatic regulators of ISC, enabling acid-responsive reactive oxygen species (ROS) generation. Incorporation of a conformationally flexible dimethylamine chain at the imide position enables acid-triggered protonation, inducing a through-space cation-carbonyl interaction between protonated dimethylamine and the neighboring imide carbonyl group. This localized electrostatic field redistributes electrons within the PDI-DMA core, markedly reduces singlet-triplet energy gaps, and promotes ISC. Consequently, PDI-DMA exhibits acid-enhanced ROS generation, achieving over an order-of-magnitude enhancement relative to its alkyl-substituted analogue PDI-Bt. Systematic molecular controls, host-guest shielding experiments, and theoretical calculations collectively identify this nonconjugated side-chain-induced electrostatic interaction as the dominant origin of the enhanced ROS generation, overturning the conventional assumption that nonconjugated imide substituents are photophysically inert. When formulated into biocompatible nanoparticles, they preferably accumulate at lysosomes and retain acid-enhanced ROS production, delivering potent photodynamic antitumor efficacy following intratumoral administration in tumor-bearing mice. This work establishes nonconjugated side-chain electrostatic modulation as an unexplored design paradigm for reprogramming excited-state processes in stimuli-responsive organic photosensitizers.