pH-responsive ZIF-8@quercetin nanoparticles induce pyroptosis for targeted gastric cancer therapy

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Gastric cancer (GC) remains a major global health burden, with limited effective therapies and poor prognosis. Quercetin (Que), a natural flavonoid, exhibits anticancer activity but suffers from poor water solubility, limited oral bioavailability, and rapid metabolic clearance, which severely restrict its clinical translation. These pharmacokinetic limitations necessitate an efficient delivery system capable of stabilizing Que in circulation and enabling tumor-specific release. To address these limitations, a zeolitic imidazolate framework-8 (ZIF-8) was developed based on nanoparticles that encapsulate Que (ZIF-8@Que), enabling high loading efficiency and pH-responsive release. ZIF-8@Que was efficiently internalized by GC cells and localized within lysosomes, where the acidic environment accelerated drug release. This process coincided with marked reactive oxygen species (ROS) generation, leading to mitochondrial membrane depolarization, ATP depletion, and ultrastructural damage. Cellular analyses further revealed features consistent with pyroptotic cell death, including lactate dehydrogenase (LDH) release, increased staining for cleaved caspase-1 and cleaved gasdermin-D (GSDMD), and enhanced TUNEL-positive signals. Compared with free Que or empty ZIF-8, ZIF-8@Que demonstrated stronger inhibition of proliferation, migration, and invasion in vitro, while in vivo studies confirmed preferential tumor accumulation, robust tumor suppression, and minimal systemic toxicity. Collectively, these findings highlight ZIF-8@Que as a safe and effective nanoparticle that integrates drug delivery with ROS-mediated pyroptosis, offering a promising strategy to overcome the limitations of Que monotherapy and advance GC therapy. • A pH-responsive ZIF-8@quercetin nanoparticles was constructed via one-pot co-precipitation, with well-defined structure, high drug loading, acid-triggered release, and improved quercetin metabolic stability. • ZIF-8@quercetin serves as both a lysosome-targeted carrier and a POD-mimicking nanozyme, generating more ROS than free quercetin/empty ZIF-8 under physiological conditions. • ZIF-8@quercetin-induced ROS causes gastric cancer cell mitochondrial dysfunction and activates caspase-1-dependent pyroptosis as the dominant cell death mode. • ZIF-8@quercetin inhibits gastric cancer cell proliferation/migration/invasion in vitro and suppresses the growth of AGS in vivo with minimal systemic toxicity.

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