1 Department of Chemistry and Biochemistry and the Centre for NanoScience Research, Concordia University, Montreal H4B 1R6, Canada. rafik.naccache@concordia.ca.
2 Quebec Centre for Advanced Materials, Concordia University, Montreal H4B 1R6, Canada.

Efficient delivery of therapeutics remains a significant challenge, often hindered by solubility barriers encountered within aqueous biological environments. Carbon dots (CDs) offer a promising solution for drug delivery due to their aqueous dispersibility, generally low cytotoxicity and surfaces rich in functional groups which can enable facile conjugation of target payloads. However, traditional CD conjugation methods typically rely on robust covalent amide bonds that are difficult to cleave and require the use of hazardous coupling reagents. As an alternative covalent linkage, the solid-state mechanochemical formation of covalent imine bonds on the surfaces of CDs was achieved in this work. Vanillin (VAN), a model aldehyde molecule, was mechanochemically conjugated to the surface of CDs without the need for a solvent, or a catalyst. ¹H-NMR analysis confirmed successful formation of an imine bond linkage due to the appearance of an imine proton at 8.1 ppm. Deconvolution of the N 1s spectrum revealed an increase in the relative N?C area at 398.5 eV from 38.9% to 61.9%, confirming the formation of new imine bonds. A drug loading capacity (DLC) of 5.02% was achieved and the pH-responsive drug release profiles were similar across all tested pH levels (5, 6, and 7.4) with release occurring over a period of 24 hours before reaching a plateau. In vitro cell viability assays showed that the CDs remained above 90% cell viability after 72 hours and exhibited low cytotoxicity in A549 model lung cancer cells, before and after mechanochemical conjugation with VAN.