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

## TL;DR

Researchers designed nanospikes that generate mechanical stress inside cancer cells, triggering cell death through autophagy and offering a new approach for cancer treatment.

## Contribution

A bioinspired strategy using nanospikes to control intracellular mechanical stress and activate autophagic cell death via the Gal3-Trim16 pathway.

## Key findings

- Nanospikes of 254.2 nm length induced the highest cancer cell death through lysosomal membrane disruption.
- Finite element simulations showed that nanospikes generate sufficient mechanical stress to trigger lysosomal rupture and autophagic cell death.
- In situ laser ablation of nanospikes reduced mechanical stress and cytotoxicity, demonstrating controllability of the approach.

## Abstract

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.

Nanospikes with tunable morphology at the nanoscale induce lysosomal membrane damage by generating localized mechanical stress, activating Galectin‐3 (Gal3)‐Trim16‐mediated autophagic cell death. Finite element analysis and laser‐triggered spike ablation enable precise control of intracellular force signaling and cytotoxicity, offering a mechanoresponsive strategy for cancer treatment.