Lysosometargeting

Lysosometargeting is the design and use of strategies to direct therapeutic agents or biological cargos to lysosomes, the cellular organelles responsible for hydrolytic degradation and recycling. The approach is applied to promote lysosomal enzyme delivery, enable controlled release of payloads within the lysosome, or induce degradation of targets via lysosome-dependent pathways.

Natural trafficking to lysosomes commonly occurs through endocytosis followed by routing to lysosomes, with the mannose-6-phosphate receptor pathway playing a central role for many lysosomal enzymes. Lysosomes maintain an acidic pH (approximately 4.5 to 5.0) and contain a suite of hydrolases; these features influence the stability and activity of lysosometargeting constructs.

Strategies include chemical or genetic tagging of cargo with lysosomal targeting signals such as mannose-6-phosphate residues, receptor-mediated delivery using M6P receptors, and the development of lysosome-targeting chimeras (LYTACs) that link extracellular or membrane proteins to lysosomal receptors for degradation. Other approaches use lysosomotropic drugs or pH-responsive nanocarriers that release payloads inside lysosomes.

Applications span enzyme replacement therapies for lysosomal storage disorders, prodrug designs that require lysosomal activation, and research tools for degrading extracellular or membrane proteins via lysosome-dependent pathways. LYTAC and related technologies expand the ability to target non-intracellular proteins for lysosomal clearance.

Challenges include achieving selective delivery to lysosomes in target cells, avoiding off-target lysosomal interception, overcoming lysosomal heterogeneity across cell types, and ensuring payload stability and safety in vivo.