Introduction. Our pulmonary Targeted RNAi Molecule (TRiMTM) delivery platform facilitates selective delivery of therapeutic siRNAs to the lung epithelium via an integrin ?v?6 targeting moiety, mediating durable gene silencing following inhaled dosing. Here, we demonstrate that the pulmonary TRiMTM platform is also compatible with subcutaneous administration and is capable of effectively silencing lung expression of the receptor for advanced glycation end-products (RAGE) in rats and nonhuman primates. Methods. Rats received s.c. injections of integrin-targeted siRNA specific for silencing RAGE mRNA. Cynomolgus monkeys received injections of ARO-RAGE, an RNAi therapeutic in Phase 1/2a trials for pulmonary inflammation. Lung expression of RAGE mRNA was quantified by RT-qPCR. Soluble RAGE (sRAGE) protein derived from full-length receptor was monitored by immunoassay in serial serum samples. Results. Lung mRNA was silenced in a ligand- and dose-dependent manner (reaching approximately 70-80% knockdown within a week) after single s.c. injection of an integrin-targeted RAGE siRNA conjugate in rats. Weekly, biweekly or monthly dosing maintained deeper lung RAGE and sRAGE silencing, with recovery to baseline expression occurring about 7 weeks post cessation of dosing. Similar observations were made in cynomolgus monkeys receiving s.c. ARO-RAGE, with weekly 10 mg/kg doses maintaining sRAGE silencing. Conclusion. Integrin-targeted siRNAs for RAGE silencing effectively kept lung RAGE knockdown when dosed subcutaneously, offering an alternative route of administration for ARO-RAGE and future pulmonary RNAi therapeutics.