Localized Nanoparticle‐Mediated Delivery of miR‐29b Normalizes the Dysregulation of Bone Homeostasis Caused by Osteosarcoma whilst Simultaneously Inhibiting Tumor Growth

Abstract

Patients diagnosed with osteosarcoma undergo extensive surgical intervention and chemotherapy resulting in dismal prognosis and compromised quality of life owing to poor bone regeneration, which is further compromised with chemotherapy delivery. This study aims to investigate if localized delivery of miR‐29b—which is shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and cervical tumor growth—can suppress osteosarcoma tumors whilst simultaneously normalizing the dysregulation of bone homeostasis caused by osteosarcoma. Thus, the therapeutic potential of microRNA (miR)‐29b is studied to promote bone remodeling in an orthotopic model of osteosarcoma (rather than in bone defect models using healthy mice), and in the context of chemotherapy, that is clinically relevant. A formulation of miR‐29b:nanoparticles are developed that are delivered via a hyaluronic‐based hydrogel to enable local and sustained release of the therapy and to study the potential of attenuating tumor growth whilst normalizing bone homeostasis. It is found that when miR‐29b is delivered along with systemic chemotherapy, compared to chemotherapy alone, the therapy provided a significant decrease in tumor burden, an increase in mouse survival, and a significant decrease in osteolysis thereby normalizing the dysregulation of bone lysis activity caused by the tumor.

Deciphering chemoresistance in osteosarcoma: Unveiling regulatory mechanisms and function through the lens of noncoding RNA

“…MiR-22 carried by mesenchymal stem cell exosomes accesses the cytoplasm after being taken up by OS cells and suppresses the proliferation, migration, and invasion by targeting Twist 1 (Ruan et al, 2024). Poly-β-aminoesters nanoparticles were utilized as intracellular delivery vectors to deliver miR-29b for local and sustained release of the therapy, which has the potential to normalize bone homeostasis while slowing OS growth (Freeman et al, 2023). Gong et al (2020) synthesized a magnetic compound consisting of the miR-302b overexpression plasmid, low-molecular-weight PEI, and glucancoated iron oxide.…”

Gene Therapy in Pediatric Orthopedics

“…A novel gene therapy treatment being studied for OS is the in vivo delivery of microR-NAs (miRNAs). MiRNAs are gene expression regulators and can be potentially developed to suppress tumor formation and promote bone remodeling [32]. MiR-29b is shown to have tumor-suppressive properties, plays a role in bone remodeling and bone regeneration, and has been shown to inhibit angiogenesis [32].…”

Engineered nanomaterials enhance drug delivery strategies for the treatment of osteosarcoma

“…Poly β aminoester (pBAE) nanoparticles have repeating ester groups, are capable of degradation in water, and have low toxicity and high biocompatibility ( Dosta et al, 2021 ). Freeman et al (2023) developed a pBAE nanoparticle delivery vehicle for delivery of miR-29b to OS cells and surrounding stromal cells. Subsequently, Fiona et al developed HA hydrogels for the sustained release of bone morphogenetic protein-2 (BMP-2) and pBAE nanoparticles.…”