Advances in Nanomedicine for Modulating DNA Methylation and Inducing Pyroptosis

DNA methylation is a key mechanism in epigenetic regulation and plays a pivotal role in tumor initiation, progression, and therapeutic resistance. We begin by elucidating how the dysregulation of key DNA methylation enzymes in tumors drives concurrent global hypomethylation and cytosine-phosphate-guanine (CpG) island hypermethylation. This aberrant epigenetic landscape promotes tumorigenesis through silencing tumor suppressor genes and triggering abnormal activation of oncogenic signaling pathways. Notably, DNA methylation is intimately linked to cellular pyroptosis. In particular, the hypermethylation-mediated silencing of pyroptosis effector genes represents a critical epigenetic mechanism underlying acquired drug resistance. Targeting DNA methylation with epigenetic drugs offers a novel strategy to resensitize tumors to chemotherapy, radiotherapy, and immunotherapy. Moreover, advances in nanomedicine have yielded smart platforms for the precise administration of epigenetic modulators and combination therapies. These platforms enable a coordinated “epigenetic priming-pyroptosis execution” strategy, which holds promises for reversing therapeutic resistance and remodeling the tumor immune microenvironment. By integrating DNA methylation regulation, pyroptosis mechanisms, and nano-targeted strategies, this review aims to provide a theoretical framework and novel perspectives for developing innovative, epigenetically driven anti-tumor therapies.