Gene-Activating\nFramework Nucleic Acid-Targeted Upregulating\nSirtuin‑1 to Modulate Osteoimmune Microenvironment for Diabetic\nOsteoporosis Therapeutics

Diabetic\nosteoporosis, a prevalent chronic complication\nof diabetes,\nis marked by reduced bone mass, increased bone fragility, and susceptibility\nto fractures. A significant cause of this condition is the disruption\nof osteoblastic homeostasis due to prolonged hyperglycemia, which\nimpedes bone regeneration and remodeling. Despite its prevalence,\nno effective treatments specifically target diabetic osteoporosis.\nRecently, small-activating RNA (saRNA) therapy has attracted attention\nfor its targeting capacity, high efficacy, and minimal side effects.\nHowever, RNA’s inherent properties, such as structural instability,\nsusceptibility to degradation, and poor penetration, limit its applications.\nTo address these limitations, a gene-activating tetrahedral framework\nnucleic acid (tFNA) with sirtuin-1 (SIRT1) gene activation function\nis developed, termed Tsa. Tsa exhibits an RNA-protecting effect and\ncan effectively penetrate cell membranes to upregulate SIRT1 gene\nexpression. At the histological level, Tsa treatment alleviates diabetic\nosteoporosis by increasing bone trabecular density and promoting new\nbone formation. At the cellular level, it switches macrophage polarization\ntoward the anti-inflammatory M2 phenotype while inhibiting the inflammatory\nM1 phenotype, creating a favorable bone immune microenvironment for\nosteoblasts. At the genetic level, Tsa activates SIRT1 expression,\nwhich deacetylates Acetyl-p65 to block the NF-κB pathway and\nrestore the osteoimmune environment. Overall, this research demonstrates\na nanodrug “Tsa”, capable of activating SIRT1 and modulating\nthe bone immune environment, thereby showcasing its immense potential\nfor diabetic osteoporosis treatment.