pH-responsive neutrophil membrane camouflage Ga-Mn bimetallic nanodecoy triggers apoptosis-immunity-metastasis suppression for tumor therapy.

Abstract

Mitochondria-mediated apoptosis and immunogenic cell death (ICD) are promising avenues in cancer therapy; however, they encounter challenges such as resistance to apoptosis and inadequate cytoplasmic sensing of mitochondrial DNA (mtDNA). Additionally, metastatic tumors remain challenging due to the lack of efficient systemic therapies that activate the immune system with low side effects. In this study, we introduce a pH-responsive neutrophil membrane camouflage nanoplatform (MGF@laN NPs) designed for the co-delivery of gallium (Ga³⁺) and manganese (Mn²⁺) ions, with the objective of orchestrating the eradication of primary tumors and the suppression of metastasis. This nanoplatform comprises a gallium-based metal-organic framework that encapsulates Mn²⁺ (MGF), coated with pH-sensitive liposomes and activated neutrophil membranes (Lip-aNEM). This innovative design enhances in vivo circulation time and selectively targets VCAM-1 overexpressing tumor cells as well as the metastatic microenvironment. Under acidic conditions characteristic of tumors, MGF@laN NPs disintegrate to release Ga³⁺, thereby disrupting mitochondrial respiration and inducing apoptosis mediated by mitochondrial damage. Concurrently, Mn²⁺ enhances the activation of the cGAS-STING pathway by improving the sensitivity of intracellular mtDNA detection, while the synergistic effects of Ga³⁺ and Mn²⁺ further disrupt ion homeostasis to bolster ICD. Additionally, the β1-integrin present on the neutrophil membrane inhibits the formation of circulating tumor cell-neutrophil clusters, thereby obstructing the establishment of metastatic niches. This study presents, a triad cascade of apoptosis-immunity- metastasis suppression for tumor treatment for the first time, providing new insights into metal ion-based biomimetic nanomedicine for cancer therapy.