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

ABSTRACT 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 Ca ²⁺ 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.