Lysosome-Mitochondria Cascade Targeting Nanoparticle Drives Robust Pyroptosis for Cancer Immunotherapy.

Area of Science:

• Nanomedicine
• Subcellular Biology
• Cancer Therapy

Background:

• Precise subcellular distribution of therapeutic cargoes is vital for cell fate and treatment effectiveness.
• Targeting specific intracellular locations for drug delivery remains a significant challenge in medicine.

Purpose of the Study:

• To engineer a nanoplatform for targeted delivery of therapeutic agents to intracellular compartments, specifically mitochondria.
• To investigate the efficacy of mitochondria-targeted therapy for cancer treatment and immune response stimulation.

Main Methods:

• Development of a trimodular, acid/enzyme-gated nanoplatform (TAEN) for controlled cargo release.
• Utilizing TAEN for selective sorting of photosensitizer molecules into mitochondria.
• Induction of mitochondrial stress and subsequent apoptotic and pyroptotic pathways.

Main Results:

• Achieved selective mitochondrial sorting of photosensitizers with a colocalization coefficient up to 0.98.
• Demonstrated enhanced cancer cell killing efficacy via mitochondrial stress-induced pyroptosis, nearly 2 orders of magnitude greater than lysosomal stress.
• Showcased robust antitumor immune efficacy in preclinical models by stimulating innate and adaptive immune responses.

Conclusions:

• The developed TAEN nanoplatform enables efficient and targeted delivery of therapeutic cargoes to mitochondria.
• Mitochondria-targeted pyroptosis via nanophotosensitizers offers a potent strategy for cancer therapy with significant immune-stimulating properties.
• This nanoplatform provides a valuable tool for nanomedicine research and subcellular-level nanobiology.