Reactive oxygen species (ROS) hold great potential in
tumor pyroptosis
therapy, yet they are still limited by short species lifespan and
limited diffusion distance. Inducing cells into a metastable state
and then applying external energy can effectively trigger pyroptosis,
but systemic sensitization still faces challenges, such as limited
ROS content, rapid decay, and short treatment windows. Herein, a nanohybrid-based
redox homeostasis-perturbator system was designed that synergistically
induce early lysosomal escape, autophagy inhibition, and redox perturbation
functions to effectively sensitize cells to address these challenges.
Specifically, weakly alkaline layered double hydroxide nanosheets
(LDH NSs) with pH-responsive degradation properties enabled early
lysosomal escape within 4 h, releasing poly(L-dopa) nanoparticles
for inducing catechol–quinone redox cycling in the cytoplasm.
The intracellular ROS levels were systematically rebounded by 3–4
times in tumor cells and lasted for over 4 h. Subsequently induced
lysosomal stress and Ca2+ signaling activation resulted
in severe mitochondrial dysfunction, as well as a perilous metastable
state. Thereby, sequential near-infrared light was applied to trigger
amplified stress through a local photothermal conversion. This led
to sufficiently high levels of cleaved caspase-1 and GSDMD activation
(2.5–2.8-fold increment) and subsequent pyroptosis response.
In addition, OH– released by LDH elevated pH to
alleviate the limitation of glutathione depletion by quinones at acidic
pH and inhibit protective autophagy. Largely secreted inflammatory
factors (2.5–5.6-fold increment), efficient maturation of dendritic
cells, and further immune stimulation were boosted for tumor inhibition
as a consequence. This study offers a new paradigm and insights into
the synergy of internal systematic cellular sensitization and sequential
external energy treatment to achieve tumor suppression through pyroptosis.