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

## TL;DR

A pH-sensitive nanoparticle boosts sonodynamic therapy for deep tumors by triggering a calcium and ROS feedback loop, improving treatment effectiveness.

## Contribution

A novel pH-responsive nanoplatform that synergizes calcium overload with sonodynamic therapy via a self-amplifying ROS loop.

## Key findings

- The nanoplatform achieved 90.9% tumor inhibition and 80% 60-day survival rate in vivo.
- Mitochondrial calcium overload caused a 71% collapse in membrane potential and a 1.6-fold increase in ROS.
- The therapy enhanced immunogenic cell death markers like CRT exposure and HMGB1 release.

## Abstract

Sonodynamic therapy (SDT) for deep-seated tumors is limited by tumor microenvironment (TME) barriers. We developed a hyaluronic acid (HA)-modified mesoporous calcium carbonate nanoplatform (HA/CaCO3@Ce6) to synergistically enhance calcium overload and SDT. The CD44-targeted nanoplatform demonstrated pH-responsive degradation in acidic TME, resulting in the release of Ca2+ and chlorin e6 (Ce6). The released Ca2+ induced mitochondrial calcium overload, causing 71% collapse in membrane potential and 1.6-fold increase in reactive oxygen species (ROS) generation, establishing a “Ca2+-ROS positive feedback loop.” This synergy triggered robust immunogenic cell death (ICD), enhancing CRT exposure by 94.2%, HMGB1 release by 46.2%, and ATP decrease by 74.5%. In vivo, it achieved 90.9% tumor inhibition and 80% 60-day survival rate, alleviated tumor hypoxia, and inhibited tumor proliferation and angiogenesis. This “ion-interference SDT” paradigm overcomes the limitations of SDT through self-amplified ROS cycle and provides an effective strategy for treating deep-seated solid tumor with significant clinical translation potential.

•Calcium overload synergizes with SDT for deep tumors•pH-responsive nanoplatform targets tumors and degrades in acidic microenvironment•Mitochondrial Ca2+ overload triggers a self-amplifying ROS loop, enhancing SDT efficacy•Nanotherapy induces mitochondrial dysfunction and immunogenic cell death

Calcium overload synergizes with SDT for deep tumors

pH-responsive nanoplatform targets tumors and degrades in acidic microenvironment

Mitochondrial Ca2+ overload triggers a self-amplifying ROS loop, enhancing SDT efficacy

Nanotherapy induces mitochondrial dysfunction and immunogenic cell death

Nanoparticles; Drug delivery system; Applied science