Targeted degradation of intracellular organelles: Strategies and implications

Organelle dysfunction is increasingly recognized as a primary driver of neurodegeneration, metabolic disorders, and cancer. The selective elimination of these organelles is primarily mediated by the autophagy-lysosome pathway. Targeted organelle degradation (TOD) has thus emerged as a powerful strategy to harness and redirect this machinery, enabling the selective clearance of organelles through engineered cargo recognition and lysosomal delivery. In this review, we aim to establish a mechanism-driven classification framework for TOD. We comprehensively survey current strategies and systematically integrate representative modalities, including autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), nanoparticle-based organelle targeting chimeras (NanoTACs), and related platforms within this framework. Key experimental strategies for assessing degradation efficiency are critically compared, with a particular focus on mitochondria and lipid droplets as well-developed case studies. Finally, we discuss the potential for expanding TOD to other organelles such as the endoplasmic reticulum and Golgi apparatus, and we highlight key challenges and future directions to drive continued advancement in the field.