Physical Stimuli–Assisted Intracellular Access and Endosomal Escape of Nanoparticles for Application in Nanomedicine: A Review

Abstract Endosomal sequestration remains a major barrier to the intracellular delivery of nanotherapeutics/nanomedicine, prompting the development of physically responsive nanomaterials activated by light, magnetic fields, and ultrasound. These external stimuli are widely proposed to induce endosomal escape through localized heating, mechanical perturbation, cavitation, membrane permeabilization, or reactive oxygen species generation. However, growing quantitative evidence suggests that in many systems only a limited fraction of internalized nanoparticles undergoes bona fide cytosolic release following stimulation, often accounting for less than 10–15% of the total intracellular population. This Review critically examines the mechanistic basis of physical stimuli–assisted endosomal escape and distinguishes true cytosolic delivery from broader stimulation-induced intracellular effects. We discuss how photothermal, magnetothermal, piezoelectric, sonodynamic, and acoustically responsive nanomaterials modulate nanoparticle–cell interactions through membrane perturbation, uptake enhancement, vesicle destabilization, altered intracellular trafficking, and nonclassical transport pathways. Importantly, we discuss why substantial therapeutic responses can still arise despite modest endosomal release, owing to enhanced intracellular accumulation and improved local bioavailability. Finally, we outline emerging strategies for quantitative mechanistic evaluation and propose a more realistic framework in which physical stimulation is viewed not solely as an endosomolytic trigger, but as a broader regulator of intracellular access relevant to next-generation nanomedicine design.