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Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes; however, the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability, cytosolic delivery and subsequent therapeutic efficacy. In this case, the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo\/lysosomal escape, which relies on the development of safe and efficient nano\u2010delivery systems. A deeper mechanistic understanding in the endo\/lysosomal escape will guide the development of more efficient nano\u2010delivery systems. In this review, we summarize various mechanisms by which nanoparticles escape from the endo\/lysosome, and showcase the recent progress in dissecting the endo\/lysosomal approaches based on nano\u2010delivery systems. 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