LNP-mediated silencing of oncogenic lncRNA PVT1 enhances chemotherapeutic efficacy in osteosarcoma

Osteosarcoma is an aggressive bone malignancy characterized by early metastasis, chemoresistance, and poor prognosis, particularly in recurrent or metastatic cases. The long non-coding RNA PVT1 has been implicated as an oncogene in various cancers, but its therapeutic potential in osteosarcoma remains underexplored. This study investigates the feasibility of targeting PVT1 using lipid nanoparticle-encapsulated siRNA (LNP-siPVT1) as a standalone or combination therapy for osteosarcoma. PVT1 expression was found to be significantly upregulated in osteosarcoma cell lines (U2OS, Saos-2, MG-63), patient tissues, and public datasets (GSE126209 and GSE309091). Tumor-targeted LNPs encapsulating siPVT1 were synthesized via microfluidic mixing and exhibited a mean diameter of ∼100 nm, favorable encapsulation efficiency, and accelerated siRNA release under acidic pH (5.5). In vitro, LNP-siPVT1 effectively suppressed PVT1 expression, reduced cell viability (IC₅₀ = 29.30 nM), and induced apoptosis in MG-63 cells; moreover, combining LNP-siPVT1 with doxorubicin (DOX) or sorafenib produced synergistic cytotoxic and pro-apoptotic effects. In a humanized immune system mouse model bearing MG-63 xenografts, LNP-siPVT1 plus DOX significantly inhibited tumor growth compared to either monotherapy, without causing overt toxicity or body weight loss, as confirmed by histology and serum biochemistry. Collectively, PVT1 serves as a prognostic biomarker and a promising therapeutic target in osteosarcoma, and LNP-mediated delivery of siPVT1, especially in combination with conventional chemotherapeutics such as DOX, represents an effective and safe strategy to enhance anti-osteosarcoma efficacy, supporting further clinical translation of LNP-siPVT1-based therapy.