N, S Co‐Doped Carbon Quantum Dots‐Riboflavin Composite Photosensitizers for Enhanced Iontophoresis‐Assisted Corneal Cross‐Linking

Iontophoresis-assisted corneal cross-linking (I-CXL) is an emerging transepithelial technique for treating keratoconus. I-CXL employs a small electric current to enhance the corneal penetration of riboflavin 5'-phosphate sodium (RF), avoiding the de-epithelialization side effects associated with conventional CXL (C-CXL). However, I-CXL is less effective than C-CXL due to insufficient RF surface charge hindering iontophoresis response and absorption efficiency, as well as inadequate reactive oxygen species (ROS) generation in the corneal stroma. This work reports the development of an innovative composite photosensitizer (NS-CQDs-RF), utilizing N, S co-doped carbon quantum dots (NS-CQDs) as nanocarriers, to overcome the bottlenecks facing I-CXL. Experimental results show that the as-synthesized NS-CQDs-RF composites exhibit a remarkable electric field response, enhanced RF corneal permeability, high ROS production efficiency, and excellent biocompatibility. Notably, I-CXL incorporating NS-CQDs-RF significantly improves corneal biomechanical stability, outperforming C-CXL while reducing total UVA irradiation energy without compromising efficacy. Density Functional Theory (DFT) calculations reveal that the optimized electronic structure and favorable energetics between NS-CQDs and RF drive efficient charge transfer, amplifying ROS generation. These findings highlight the superiority of the NS-CQDs-RF composite photosensitizers in I-CXL, offering a novel strategy for future keratoconus treatment.