Stimulated Trafficking of RNAi to Parathyroid toward Its Angiogenetic Vessels for Suppressed Secretion of Parathyroid Hormone

Abstract

Secondary hyperparathyroidism is driven by pathological overproduction of parathyroid hormone. Surgery is invasive, drug therapy offers only transient control, and both carry substantial side effects. Previous efforts to deliver siRNA to the parathyroid glands achieved only marginal efficacy because the constructs lacked a targeting ligand to overcome the organ’s limited vascular permeability and were rapidly cleared by renal filtration. This study provides a targeted RNA interference therapeutic strategy for treatment of secondary hyperparathyroidism by leveraging the angiogenic characteristics of parathyroid glands via systemic route. Particularly, we manufactured an Arg-Gyl-Asp (RGD)-conjugated siRNA delivery system that exploits the overexpression of integrins and increased vascular permeability in parathyroid glands to achieve preferential siRNA accumulation. The multifunctional cationic copolymers of RGD-poly(ethylene glycol) (PEG)-polylysine-azido [PLys(N₃)] and PLys(ss-dibenzocyclooctyne: DBCO) were synthesized and characterized, demonstrating their ability to formulate robust nanocomplexes with small interference RNA [(siRNA): knockdown of parathyroid hormone (PTH)] by virtue of favorable reversible disulfide cross-linking (based on click reaction) post electrostatic complexation. These nanocomplexes exhibited prolonged systemic circulation, preferential accumulation in the angiogenic parathyroid glands, and active intracellular delivery, leading to significant suppression of PTH expression. In a parathyroid hyperplasia mouse model, the siPTH delivery construct from RGD–PEG-PLys(N₃)&PLys(ss-DBCO) substantially reduced the serum PTH levels to near-normal values, highlighting the therapeutic potential of our siRNA delivery system. Hence, this RNAi approach outperforms conventional modalities by achieving rapid, potent, and sustained gene knockdown without surgical risk or chronic pharmacologic burden, establishing a paradigm for precision endocrine therapy.