pH-responsive CaCO₃ nanoplatform amplifies SDT via calcium overload-ROS loop for deep tumor therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Sonodynamic therapy (SDT) efficacy for deep tumors is hindered by the tumor microenvironment (TME).
• Existing SDT methods face challenges in overcoming TME barriers and achieving sufficient therapeutic effects.

Purpose of the Study:

• To develop a hyaluronic acid (HA)-modified mesoporous calcium carbonate nanoplatform (HA/CaCO3@Ce6) for enhanced SDT.
• To synergistically improve calcium overload and SDT effectiveness in the acidic TME.

Main Methods:

• Designed a CD44-targeted nanoplatform (HA/CaCO3@Ce6) with pH-responsive degradation.
• Investigated the release of Ca2+ and chlorin e6 (Ce6) in acidic TME.
• Assessed the induction of mitochondrial calcium overload, ROS generation, and subsequent effects on cancer cells.

Main Results:

• The nanoplatform induced mitochondrial calcium overload, increasing ROS generation via a Ca2+-ROS positive feedback loop.
• Achieved significant immunogenic cell death (ICD) markers: 94.2% CRT exposure, 46.2% HMGB1 release, 74.5% ATP decrease.
• In vivo studies showed 90.9% tumor inhibition and 80% survival rate, with reduced tumor hypoxia, proliferation, and angiogenesis.

Conclusions:

• The developed 'ion-interference SDT' paradigm effectively overcomes TME limitations.
• The self-amplified ROS cycle strategy shows significant potential for treating deep-seated solid tumors.
• This approach presents a promising strategy with high clinical translation potential.