AS1411-functionalized albumin nanoparticles for nucleolin-targeted realgar delivery and therapy in triple-negative breast cancer.

Realgar (As4S4) has shown antitumor activity, but its pharmaceutical application is limited by poor aqueous solubility, low bioavailability, and systemic toxicity. In this study, we developed AS1411-functionalized albumin nanoparticles (As4S4@ BSA-AS1411 NPs) for targeted delivery of realgar to triple-negative breast cancer (TNBC). Bulk As4S4 was converted into nanosized clusters and encapsulated in a bovine serum albumin (BSA) matrix, followed by surface conjugation with the nucleolin-targeting aptamer AS1411. The resulting nanoparticles showed suitable physicochemical properties and good colloidal stability in physiologically relevant media, together with enhanced cellular internalization in 4T1 cells. Compared with non-targeted nanoparticles, AS1411 modification significantly increased cytotoxicity and reduced the migratory ability of 4T1 cells. Mechanistic studies showed that treatment with As4S4@BSA-AS1411 NPs was associated with upregulation of GADD45G and downregulation of mTOR, suggesting a stress-related antiproliferative effect. In vivo fluorescence imaging demonstrated increased tumor accumulation of AS1411-functionalized NPs. In 4T1 tumor-bearing mice, systemic administration of As4S4@BSA-AS1411 NPs produced greater tumor growth inhibition than non-targeted controls, accompanied by increased apoptosis and reduced proliferative activity in tumor tissues. In addition, the formulation showed good in vivo tolerability, with no evident systemic toxicity or hemolytic activity. These findings indicate that AS1411-functionalized albumin NPs are a promising delivery system for improving the antitumor efficacy and safety profile of realgar in TNBC.