Tetrahedral Framework Nucleic Acid-Based Delivery of Resveratrol Alleviates Insulin Resistance: From Innate to Adaptive Immunity

Abstract

Obesity-induced insulin resistance is the hallmark of metabolic syndrome, and chronic, low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Current therapeutic approaches lack efficacy and immunomodulatory capacity. Thus, a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance. Here, we synthesized a tetrahedral framework nucleic acid (tFNA) nanoparticle that carried resveratrol (RSV) to inhibit tissue inflammation and improve insulin sensitivity in obese mice. The prepared nanoparticles, namely tFNAs-RSV, possessed the characteristics of simple synthesis, stable properties, good water solubility, and superior biocompatibility. The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy. In high-fat diet (HFD)-fed mice, the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status. tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages. As for adaptive immunity, the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg, leading to the alleviation of insulin resistance. Furthermore, this study is the first to demonstrate that tFNAs, a nucleic acid material, possess immunomodulatory capacity. Collectively, our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice, suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

The Neuroprotective Effect of MicroRNA‐22‐3p Modified Tetrahedral Framework Nucleic Acids on Damaged Retinal Neurons Via TrkB/BDNF Signaling Pathway

“…The results showed that the mobility of tFNAs‐miR22 was slower than that of tFNAs, for the molecular mass of tFNAs‐miR22 was larger than that of tFNAs 52. [ 22,29 ] Then we used high‐performance capillary electrophoresis to reconfirm the successful synthesis of these nanomaterials and verified the PAGE results (Figure 1c; Figure S2, Supporting Information). In addition, sufficient biological stability is a basic feature for the carrier in drug‐delivery applications.…”

“…tFNAs can be easily assembled from four specifically designed ssDNA strands (Table S1, Supporting Information) through a simple annealing process. [ 20–23 ] In this work, we modified miR‐22‐3p to the 5’ end of S3 in a similar way as our previous study to form a new S3 (S3‐miR22, Table S1, Supporting Information), [ 28 ] and then synthesized tFNAs‐miR22 in the same steps as tFNAs ( Figure ). Successfully synthesis of tFNAs and tFNAs‐miR22 were detected via 8% polyacrylamide gel electrophoresis (PAGE) based on their different mobility (Figure 1b; and Figure S1, Supporting Information).…”

“…The tetrahedral skeleton nucleic acids (tFNAs), as a new 3D nucleic acid nanomaterial with considerable merits, including biocompatibility, structural stability, and programmability, have demonstrated tremendous potential as a vector for drug delivery and biomedical treatment. [ 20–24 ] In our early exploration in the prevention and treatment of various eye diseases, tFNAs have been proved to act a positive part as drugs in repairing corneal injury and the anti‐oxidative stress of RGCs. [ 25,26 ] Furthermore, our previous studies have shown that tFNAs can exert neuroprotective influence in the Alzheimer's disease in vitro model.…”

Application of Programmable Tetrahedral Framework Nucleic Acid-Based Nanomaterials in Neurological Disorders: Progress and Prospects

“…Recent evidence suggests that tFNA, a special DNA nanodevice, which has been widely used in diverse biomedical fields, might be a powerful tool that could be helpful in the treatment of NDs (Li et al, 2021b;Li et al, 2021c). Here, this minireview concludes the development and use of tFNA, which is highly applied DNA nanostructure with unique characteristics, flexible penetration, precise programmability and susceptibility to biological regulation (Sirong et al, 2020;Sun et al, 2021).…”

Bioswitchable Delivery of microRNA by Framework Nucleic Acids: Application to Bone Regeneration

“…Second, the miRs were transported into cells dependent on the excellent cell-entrance ability of tFNA. [49,50] Third, RNase H, which is widely present in mammalian cells, was utilized to unload the miRs to avoid unnecessary participation of tFNA in subsequent biochemical reactions involving the miRs. [33] Finally, although double-stranded miRs were delivered initially, the inferior thermodynamic stability of the 5′ end of the guide strand enables the cell to actively select a suitable guide strand for the formation of the RISC.…”