Size Optimization of Organic Nanoparticles with Aggregation-Induced Emission Characteristics for Improved ROS Generation and Photodynamic Cancer Cell Ablation.

Aggregation-induced emission (AIE) fluorogens provide new opportunities to promote efficient reactive oxygen species (ROS) production in aggregates, which represent the promising candidates to construct theranostic nanoparticles for photodynamic therapy (PDT), but the size effect has been rarely explored. Herein, a universal method to fabricate organic nanoparticles with controllable sizes is reported and it demonstrates that ≈45 nm is the optimal size of AIE nanoparticles for PDT. Different from conventional Ce6 nanoparticles which show largely reduced fluorescence and ROS generation with increasing nanoparticle size, AIE nanoparticles show gradually enhanced brightness and ROS generation upon increasing the sizes from 6 to ≈45 nm. Further increasing sizes could continue to intensify the nanoparticle's brightness at the expense of ROS production, with the optimal size for ROS generation being achieved at ≈45 nm. Both 2D monolayer cell and 3D multicellular spheroid experiments confirm that 45 nm AIE nanoparticles have the highest cellular uptake, the deepest penetration depth, and the best photodynamic killing effect. Such a study not only manifests the advantages of AIE photosensitizers, but also delivers the optimal size ranging for efficient PDT, which shall provide an attractive paradigm to guide the development of phototheranostic nanoparticles besides molecular design to further promote PDT applications.

Cationization to boost both type I and type II ROS generation for photodynamic therapy.

The pursuing of photosensitizers (PSs) with efficient reactive oxygen species (ROS) especially type I ROS generation in aggregate is always in high demand for photodynamic therapy (PDT) and photoimmunotherapy but remains to be a big challenge. Herein, we report a cationization molecular engineering strategy to boost both singlet oxygen and radical generation for PDT. Cationization could convert the neutral donor-acceptor (D-A) typed molecules with the dicyanoisophorone-triphenylamine core (DTPAN, DTPAPy) to their A-D-A' typed cationic counterparts (DTPANPF6 and DTPAPyPF6). Our experiment and simulation results reveal that such cationization could enhance the aggregation-induced emission (AIE) feature, promote the intersystem crossing (ISC) processes, and increase the charge transfer and separation ability, all of which work collaboratively to promote the efficient generation of ROS especially hydroxyl and superoxide radicals in aggregates. Moreover, these cationic AIE PSs also possess specific cancer cell mitochondrial targeting capability, which could further promote the PDT efficacy both in vitro and in vivo. Therefore, we expect this delicate molecular design represents an attractive paradigm to guide the design of type I AIE PSs for the further development of PDT.