Engineering bone tissue with mRNA: from molecular design and delivery to clinical applications

Bone possesses an intrinsic ability to regenerate after injury, but this capacity is often compromised in pathological conditions. Non-healing fractures are typically treated with autografts, which involve additional surgeries, patient discomfort, and risk of complications. Alternative strategies, such as the administration of growth factor proteins or plasmid DNA, have shown promise but are limited by high costs, immunogenicity, and safety concerns. Recently, messenger RNA (mRNA) therapies have emerged as a compelling alternative for inducing bone regeneration. Unlike DNA, mRNA functions in the cytoplasm, eliminating the need for nuclear entry and minimizing the risk of insertional mutagenesis. It is also transiently expressed and fully degradable, offering a favorable safety profile. Chemical modifications to mRNA can improve its stability, translational efficiency, and reduce innate immune activation, making it a versatile and potent tool for therapeutic applications. In this review, we explore the types of chemical modifications used to enhance mRNA performance, the delivery strategies employed for efficient cellular uptake (including in vivo and ex vivo routes), and the design of biomaterial scaffolds that support bone repair while enabling spatial and temporal control of gene expression. We also discuss the translational potential of mRNA-based approaches, including safety considerations, manufacturing scalability, and cost-effectiveness. Collectively, these advances position chemically modified mRNA as a nextgeneration therapeutic for bone regeneration, with the potential to overcome the limitations of current treatments and improve outcomes for patients with challenging fractures.