Engineering dual-gas releasing nanoplatform for enhancing endogenous Ca2+-mediated ion interference therapy

Calcium (Ca²⁺) overload-based ion interference therapy (IIT) is emerging as a promising treatment against malignancies, but it is challenged by the intrinsic ionic homeostasis of cancer cells. Herein, a dual-gas nanoplatform, CMS@PDA@RuNO@MnCO (abbreviated as CPNC NPs), is engineered to achieve endogenous multichannel Ca²⁺-overload-mediated IIT to prevent tumor metastasis. Treatment of CPNC NPs with near-infrared (NIR) laser irradiation allows for controlled release of NO and CO. The released NO triggers the opening of the ryanodine receptor channel and the leakage of Ca²⁺ leakage from the endoplasmic reticulum. Meanwhile, the released CO induces oxidative stress to activate the transient receptor potential ankyrin subtype 1 channel, facilitating Ca²⁺ influx. This dual-action strategy overloads cancer cells with Ca²⁺, leading to mitochondrial damage, adenosine triphosphate depletion, and tumor apoptosis, effectively inhibiting lung metastasis. In vivo assessments exhibited excellent anti-tumor and anti-metastatic potency of CPNC NPs in suppressing tumor proliferation and metastasis under NIR laser exposure. RNA profiling analysis indicated that CPNC NPs treatment and NIR laser exposure markedly regulate Ca²⁺-overload pathways and inhibit metastasis-related gene expression. This study pioneers the use of a dual-gas nanoplatform to disrupt endogenous Ca²⁺ homeostasis, providing a promising therapeutic strategy for cancer treatment.