<p>Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis, whose pathogenesis remains unclear. Fibroblast-like synoviocytes (FLS) are central to the pathogenesis and progression of RA. This study aims to investigate the novel role of the pyroptosis mechanism mediated by the caspase-8/caspase-3/gasdermin-E (GSDME) pathway in RA-FLS, and further develop a transdermal drug delivery system (TDDS) to deliver quercetin (QUE) nanoparticles, which act on this pathway by targeting caspase-8. Specifically, we designed and constructed a 3D bioprinted bionic and architecture-mimetic double-crosslinked hydrogel dissolvable microneedle (MN) based on gelatin methacrylamide (GelMA) and silk fibroin methacryloyl (SilMA). This microneedle is used for transdermal delivery of quercetin liposomal nanoparticles modified with cell-penetrating peptide (CPP) (QUE-Lipo-TAT), so as to interrupt the vicious cycle between cell death and inflammation in RA-FLS. The results showed that caspase-8 is a potential therapeutic target for RA, and the novel caspase-8/caspase-3/GSDME pathway can mediate pyroptosis in RA-FLS. QUE-Lipo-TAT can not only block the caspase-8/caspase-3/GSDME axis by inhibiting caspase-8 via targeted action to prevent pyroptosis in RA-FLS, but also inhibit receptor-interacting protein kinase 3 (RIPK3) to prevent necroptosis in RA-FLS. Thereby, it suppresses inflammatory death, pro-inflammatory cytokine release, and disordered cell proliferation and migration of RA-FLS, achieving a “kill two birds with one stone” therapeutic effect. A novel hydrogel microneedle with bee stinger-mimetic and Oriental Pearl Tower-mimetic structures was prepared for the first time using GelMA-SilMA (GS) hydrogel. This microneedle possesses excellent biodegradability and mechanical properties, enabling it to easily penetrate the stratum corneum. Its favorable swelling performance and adhesiveness allow the double-sphere and single-ring microneedle structure to be firmly embedded in the skin. Additionally, the microneedle’s good degradability enables the sustained release of nanoparticles. QUE-Lipo-TAT delivered via this microneedle effectively alleviates hind paw swelling and improves joint conditions in collagen-induced arthritis (CIA) rats, reduces the levels of pro-inflammatory cytokines, inhibits synovial hyperplasia and bone and cartilage damage, and exhibits favorable biosafety. The novel target, new pathway, and new drug delivery method identified in this study provide a promising new approach for the precision treatment of RA.</p> Graphical abstract <p></p>