Pyroptosis is a lytic and inflammatory type of programmed cell death that is usually triggered by inflammasomes and executed by gasdermin proteins. The main characteristics of pyroptosis are cell swelling, membrane perforation, and the release of cell contents. In normal physiology, pyroptosis plays a critical role in host defense against pathogen infection. However, excessive pyroptosis may cause immoderate and continuous inflammatory responses that involves in the occurrence of inflammatory diseases. Attractively, as immunogenic cell death, pyroptosis can serve as a new strategy for cancer elimination by inducing pyroptotic cell death and activating intensely antitumor immunity. To make good use of this double-edged sword, the molecular mechanisms, and therapeutic implications of pyroptosis in related diseases need to be fully elucidated. In this review, we first systematically summarize the signaling pathways of pyroptosis and then present the available evidences indicating the role of pyroptosis in inflammatory diseases and cancer. Based on this, we focus on the recent progress in strategies that inhibit pyroptosis for treatment of inflammatory diseases, and those that induce pyroptosis for cancer therapy. Overall, this should shed light on future directions and provide novel ideas for using pyroptosis as a powerful tool to fight inflammatory diseases and cancer.

Background Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. Methods In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. Results BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. Conclusion BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy. Graphical Abstract

Efficient drug delivery to solid tumors remains a challenge. HER2-positive (HER2+) tumors are an aggressive cancer subtype with a resistance to therapy, high risk of relapse, and poor prognosis. Although nanomedicine technology shows obvious advantages in tumor treatment, its potential clinical translation is still impeded by the unsatisfactory delivery and therapeutic efficacy. In this study, a gene reprogramming macrophage membrane-encapsulated drug-loading nanoplatform was developed for HER2+ cancer therapy based on the co-assembly of poly (lactic-co-glycolic acid) (PLGA) nanoparticles and engineered modified macrophage membranes. In this nanoplatform, near-infrared (NIR) fluorescent dye ICG or chemotherapeutic drug doxorubicin (DOX) was loaded into the PLGA cores, and an anti-HER2 affibody was stably expressed on the membrane of macrophages. In comparison to the nanoparticles with conventional macrophage membrane coating, the ICG/DOX@AMNP nanoparticles armed with anti-HER2 affibody showed excellent HER2-targeting ability both in vitro and in vivo. Small animal imaging studies confirmed the improved pharmacokinetics of drug delivery and specific distribution of the ICG/DOX@AMNPs in HER2+ tumors. Mechanistically, compared with DOX@NPs or DOX@MNPs nanoparticles, DOX@AMNPs exhibited synergistic inhibition of HER2+ cancer cells or mice tumor growth by inducing apoptosis and blocking the PI3K/AKT signaling pathway. Altogether, this study proposes a promising biomimetic nanoplatform for the efficient targeted delivery of chemotherapeutic agents to HER2+ tumors, demonstrating its great potential for solid tumor therapy.

The majority of cancer patients die of metastasis rather than primary tumors, and most patients may have already completed the cryptic metastatic process at the time of diagnosis, making them intractable for therapeutic intervention. The urokinase‐type plasminogen activator (uPA) system is proved to drive cancer metastasis. However, current blocking agents such as uPA inhibitors or antibodies are far from satisfactory due to poor pharmacokinetics and especially have to face multiplex mechanisms of metastasis. Herein, an effective strategy is proposed to develop a uPA‐scavenger macrophage (uPAR‐MΦ), followed by loading chemotherapeutics with nanoparticles (GEM@PLGA) to confront cancer metastasis. Interestingly, significant elimination of uPA by uPAR‐MΦ is demonstrated by transwell analysis on tumor cells in vitro and enzyme‐linked immunosorbent assay detection in peripheral blood of mice with metastatic tumors, contributing to significant inhibition of migration of tumor cells and occurrence of metastatic tumor lesions in mice. Moreover, uPAR‐MΦ loaded with GEM@PLGA shows a robust antimetastasis effect and significantly prolonged survival in 4T1‐tumor‐bearing mice models. This work provides a novel living drug platform for realizing a potent treatment strategy to patients suffering from cancer metastasis, which can be further expanded to handle other tumor metastasis markers mediating cancer metastasis.