Beyond the cell membrane: subcellular organelle-targeted nanomedicines.

Emerging from liposomes, nanomedicines have been rapidly developed into powerful tools for the diagnosis, therapy, and prevention of diseases. After bypassing from physiological barriers, most nanoparticles are interrupted on the way to subcellular organelles, causing less than 1% of nanoparticles to reach the desired organelles. As organelles actively participate and mediate the progression of cellular survival, proliferation, and apoptosis, targeting organelles is a promising strategy for nanomedicine to improve therapeutic specificity and minimize side effects. The direct delivery of therapeutic materials into organelles such as nuclei, mitochondria, or lysosomes presents major challenges; however, advances in the synthesis, surface modification, and structural optimization of nanomedicines raise promising prospects for overcoming these barriers. Building on our previous study on organelle-targeting nanomedicine, in this review, we summarize the key aspects of chemical modification and structural optimization. Moreover, current nanomedicines specialized for targeting the nucleus, mitochondria, lysosomes, Golgi apparatus, and endoplasmic reticulum are classified for a holistic view of organelle-specific nanomedicine. Although promoted by artificial intelligence (AI) and machine learning (ML), organelle-targeting nanomedicines struggle to reach clinical application, and the major challenges are critically discussed here.