Abstract The lysosome, long regarded as a terminal degradative organelle, has emerged as a central and programmable hub for anticancer nanomedicine. Advances in materials science, chemical biology, and intracellular trafficking have enabled nanomaterials to exploit lysosomal pathways not only for drug degradation but also for controlled payload activation, cytosolic delivery, signaling modulation, and organelle-confined therapeutic execution. In this review, we present a unified framework for lysosome-centered cancer nanotherapy organized along five complementary design axes: receptor-guided lysosomal protein degradation platforms such as lysosome-targeting chimeras (LYTACs); lysosome-triggered payload activation and release; endolysosomal escape strategies enabling cytosolic or nuclear delivery; nanomaterial-mediated modulation of lysosomal function and autophagic flux; and lysosome-focused therapeutic modalities driven by external stimuli or catalytic reactions, including photodynamic, sonodynamic, photothermal, and chemodynamic therapies. Across these paradigms, the lysosome functions not merely as a passive sink but as an active determinant of therapeutic specificity, efficacy, and immune consequence. We discuss how rational nanomaterial design leverages lysosomal acidity, enzymatic activity, membrane vulnerability, and signaling roles to overcome drug resistance, reprogram tumor immunity, and enable previously inaccessible therapeutic interventions. Finally, we highlight key translational challenges—including receptor heterogeneity, material complexity, biological feedback, and manufacturing scalability—and outline future directions toward clinically viable, precision lysosome-targeted nanomedicines. Graphical Abstract
Xu et al. (Tue,) studied this question.