Intracellular Mechanical Stress‐Mediated Autophagy Cell Death via Nanospikes for Cancer Treatment

Mechanical signals are fundamental regulators of cell fate, yet how cells respond to mechanical stress at the subcellular level remains unclear. Inspired by natural spiky structures that concentrate mechanical stress at the nanoscale, a series of tunable gold nanospikes are designed to promote internalization and modulate mechanical stress intracellularly. The nanospikes with a length of 254.2 nm induced the highest cancer cell death compared to those with 104.0 and 45.4 nm. Mechanistically, nanospikes are internalized into lysosomes and triggered extensive lysosomal membrane disruption. Finite element simulations reveal that the tip stress generated by nanospikes with a length of 254.2 nm achieves the highest value within 5.233 to 9.902 kPa range across the majority of lysosome sizes, exceeding the mechanical threshold for lysosomal rupture. This mechanical stress on lysosomal membranes triggered autophagic cell death through the Galectin-3 (Gal3)-Trim16 signaling axis, establishing a direct mechanobiological link between nanostructure geometry and cell fate. Importantly, the nanospikes achieve 77.8% tumor inhibition, while the in situ melting via nanosecond pulsed laser enables reduced mechanical stress and attenuated cytotoxicity. This bioinspired morphological strategy provides a controllable method for tuning intracellular mechanics, providing new insights for the rational design of mechanical drugs for cancer treatment.