Reinforcing Calcium Overload via Inflammation-Mediated Targeting to Amplify Pyroptosis and Antitumor Immunity

Tumor-associated inflammation presents a promising therapeutic target, yet it remains insufficiently exploited in current nanomedicine approaches. While inflammation-driven strategies, such as inducing pyroptosis, have the potential to enhance tumor immunity, their limited induction efficiency and poor tumor targeting still pose significant challenges. Herein, we engineer a neutrophil membrane-camouflaged nanoplatform (RC@NMVs) that exploits tumor inflammation to drive reinforcing calcium dyshomeostasis and pyroptotic amplification. This biomimetic system comprises calcium phosphate (CaP) nanoparticles co-loaded with the calcium channel blocker, ruthenium red. Upon internalization by tumor cells, the CaP core dissolves within lysosomes, releasing Ca^{2 +} ions, while ruthenium red inhibits the Ca²⁺ transporting channels, synergistically elevating intracellular Ca^{2 +} levels. The resulting calcium overload triggers gasdermin-mediated pyroptosis, characterized by the release of damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. The amplified inflammatory microenvironment facilitates the recruitment and tumor accumulation of subsequently administered RC@NMVs. In vivo studies demonstrate enhanced tumor enrichment of RC@NMVs compared to non-inflamed controls, leading to robust pyroptosis and significant tumor inhibition. Moreover, pyroptosis-driven inflammation elicits durable antitumor immune responses, effectively preventing tumor recurrence and metastasis. In general, this work presents a biomimetic strategy that harnesses inflammation-mediated tumor targeting to amplify pyroptosis and immune activation, offering a promising approach for effective cancer therapy.