The pcDNA3.1-LEF1-AS1 was synthesized by GeneChem (Shanghai, China). nanoparticles (NPs) were functionalized with anti-CD305 antibody to construct (Zn-Adenine)@Ab. These NPs were then loaded with LEF1-AS1 to form (Zn-Adenine)@Ab@lncRNA LEF1-AS1. Finally, the (Zn-Adenine)@Ab@lncRNA LEF1-AS1 NPs were locally injected into a rat model with collagen-induced arthritis (CIA). The arthritic injuries in each group were evaluated by HE staining and other methods. Results LEF1-AS1 was expressed at low levels in the primary RASFs. High expression levels of LEF1-AS1 were detected in the HFLS cells, Vinorelbine (Navelbine) which corresponded to a significant downregulation of miR-30-5p. In addition, the expression level of PIK3R2 was significantly increased, and that of p-PI3K and p-AKT were significantly downregulated in these cells. The (Zn-Adenine)@Ab@lncRNA LEF1-AS1 NPs significantly inhibited the proliferation of RASFs and decreased the production of inflammatory cytokines (IL-1, IL-6, TNF-). Intra-articular injection (IAI) of (Zn-Adenine)@Ab@lncRNA LEF1-AS1 NPs significantly alleviated cartilage destruction and joint injury in the CIA-modeled rats. Conclusions LEF1-AS1 interacts with miR-30-5p to inhibit the abnormal proliferation of RASFs by regulating the PI3K/AKT signal pathway. The (Zn-Adenine)@Ab NPs achieved targeted delivery of the loaded LEF1-AS1 into the RASFs, which improved Smoc2 the cellular internalization rate and therapeutic effects. Thus, LEF1-AS1 is a potential target for the treatment of RA. Keywords: Nanomedicine, LncRNA LEF1-AS1, miR-30-5p, PIK3R2, Rheumatoid arthritis, Synovial fibroblasts Introduction Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial cell proliferation, inflammatory cell infiltration, and destruction of cartilage and bone [1]. The activated synovial fibroblasts in the inflamed synovium show enhanced proliferation and invasion into the articular cartilage, which erodes the cartilage and bone tissues, eventually causing structural damage to the affected joint. Therefore, it is critical to inhibit the proliferation, migration, and invasion of synovial fibroblasts during RA treatment [2, 3]. Although the current drugs for RA have significantly improved patient prognosis, the risk of treatment tolerance and loss of function due to increasing dosage are high, which limits the clinical outcomes [4, 5]. Gene-targeting drugs Vinorelbine (Navelbine) have high precision and low toxicity and can be delivered to the rheumatoid synovial tissues using nanocarriers. The progression of RA involves the dysregulation of multiple signaling pathways and the disruption of autoimmune regulatory functions. In RA, the PI3K/AKT signaling pathway is aberrantly activated, leading to the excessive proliferation of synovial fibroblasts and the exacerbation of local inflammation in RA [6]. PIK3R2, as a member of the PI3K p85 subunit family, plays a role in inhibiting the activation of the PI3K/AKT signaling pathway. Several studies have demonstrated that targeting PIK3R2 to inhibit PI3K/AKT signaling pathway can effectively suppress the proliferation, migration, invasion, and inflammation of RASF and promote the apoptosis of RASF [7]. The metal-organic coordination polymers have multiple applications, such as gas storage and drug Vinorelbine (Navelbine) delivery, due to their mild polymerization conditions, high porosity, and molecular retention [8, 9]. Adenine is a naturally occurring nucleobase containing an N-heterocyclic ring and Vinorelbine (Navelbine) can coordinate various metal ions to form metal-biomolecule frameworks (mBIOFs) through heterocycles and imidazole nitrogen atoms. It has the advantages of accessibility, biocompatibility, low costs, nanoscale size, high drug-loading efficiency, and self-assembly [10]. We constructed Zn-Adenine mBIOFs and coated the nanoparticles (NPs) with the antibody targeting anti-CD305, which is highly expressed in the synovium of RA patients [11], for the targeted therapy of RA. Several genetic and environmental factors have been implicated in RA etiology [12]. Studies increasingly show that epigenetic modifications, such as gene expression changes caused by non-coding RNAs, play a critical role in the pathogenesis of RA. For instance, several miRNAs have been identified that are aberrantly expressed during the onset and progression of RA. We have previously shown that miR-30-5p mediates RA development by regulating the PIK3R2/PI3K-AKT signaling pathway in the synovial fibroblasts, which maintains the balance between proliferation and apoptosis [13]. Since lncRNAs regulate target mRNAs by competing for the binding sites in miRNAs, it is worth investigating the lncRNA-miRNA-mRNA regulatory network involved in RA. In the present study, we found that LEF1-AS1 functions as a sponge for miR-30-5p in RASFs and is aberrantly downregulated in the synovial tissues of RA patients. Overexpression of LEF1-AS1 in the HFLS inhibited their proliferation,.