Lipid droplet-targeted photosensitizers: emerging strategies for triggering programmed cell death

Lipid droplets (LDs), recognized as pivotal organelles responsible for intracellular lipid storage and metabolism, play indispensable roles in maintaining lipid homeostasis, cellular energy balance, membrane biosynthesis, and signal transduction. Dysregulation of LD function is implicated in the pathogenesis of various diseases. LD-targeted phototherapy has emerged as a promising paradigm for precision cancer treatment due to its ability to induce distinct programmed cell death (PCD) pathways and enhance therapeutic efficacy. This review summarizes recent advances in the use of LD-targeted photosensitizers (PSs) to trigger PCD. We critically examine innovative molecular design strategies that enable precise localization to LDs and elucidate the mechanisms by which these PSs activate specific PCD pathways. To provide essential context, key PCD modalities, such as ferroptosis, pyroptosis, apoptosis, and lipophagy, are briefly introduced in terms of their core concepts and hallmark features. Persistent challenges and emerging issues in this rapidly evolving field are also highlighted. Finally, we outline further research directions and potential breakthroughs for LD-targeted PSs in PCD studies, with the aim of guiding further exploration in this promising area.