A hindrance-plane-hindrance molecular engineering strategy towards self-assembled nanorods for enhanced photodynamic therapy.

As the vital component of photodynamic therapy, organic photosensitizers face challenges in clinical translation due to their compromised reactive oxygen species generation and limited tumor targeting when aggregated or formulated as nanoparticles. Herein, we overcome this dilemma by proposing a steric hindrance-plane-hindrance molecular design strategy to guide the self-assembly of twisted donor-π-acceptor photosensitizers into rod-shaped nanoparticles, which concurrently enhance reactive oxygen species (ROS) generation and tumor accumulation. Using TPA-S-DCR and other 7 molecules as models, we demonstrate that tuning the donor and acceptor steric hindrances around π-conjugated planar center enables the controllable spherical or rod-shaped supramolecular self-assembly of these twisted donor-π-acceptor photosensitizers under mild sonication condition. The resulting nanorods exhibit 1.31-fold higher ROS production, 5.04-fold higher cancer cell uptake over the nano-spherical counterparts. Moreover, TPA-S-DCR nanorods also show higher tumor accumulation, deeper tumor penetration, and longer tumor retention over its nano-spherical counterpart, which together with its better reactive oxygen species production amplifies photodynamic therapy efficacy in female mice model. This work establishes a simple and universal approach for morphology regulation of twisted donor-π-acceptor type photosensitizers, and also highlights the therapeutic advantages of anisotropic supramolecular self-assemblies, paving the way for next-generation phototheranostic agents.