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Lipid droplets (LDs) are dynamic complex organelles involved in various physiological processes, and their number and activity are linked to multiple diseases, including cancer. In this study, we have developed LD-specific near-infrared (NIR) light-responsive nano-drug delivery systems (DDSs) based on chalcone derivatives for cancer treatment. The reported nano-DDSs localized inside the cancer microenvironment of LDs, and upon exposure to light, they delivered the anticancer drug valproic acid in a spatiotemporally controlled manner. The developed systems, namely, 2'-hydroxyacetophenone-dimethylaminobenzaldehyde-valproic ( HA-DAB-VPA ) and 2'-hydroxyacetophenone-diphenylaminobenzaldehyde-valproic ( HA-DPB-VPA ) ester conjugates, required only two simple synthetic steps. Our reported DDSs exhibited interesting properties such as excited-state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE) phenomena, which provided advantages such as AIE-initiated photorelease and ESIPT-enhanced rate of photorelease upon exposure to one- or two-photon light. Further, colocalization studies of the nano-DDSs by employing two cancerous cell lines (MCF-7 cell line and CT-26 cell line) and one normal cell line (HEK cell line) revealed LD concentration-dependent enhanced fluorescence intensity. Furthermore, systematic investigations of both the nano-DDSs in the presence and absence of oleic acid inside the cells revealed that nano-DDS HA-DPB-VPA accumulated more selectively in the LDs. This unique selectivity by the nano-DDS HA-DPB-VPA toward the LDs is due to the hydrophobic nature of the diphenylaminobenzaldehyde (mimicking the LD core), which significantly leads to the aggregation and ESIPT (at 90% volume of f w , Φ F = 20.4% and in oleic acid Φ F = 24.6%), respectively. Significantly, we used this as a light-triggered anticancer drug delivery model to take advantage of the high selectivity and accumulation of the nano-DDS HA-DPB-VPA inside the LDs. Hence, these findings give a prototype for designing drug delivery models for monitoring LD-related intracellular activities and significantly triggering the release of LD-specific drugs in the biological field.