Low back pain (LBP) stands as a global health burden, afflicting almost 80% of adults at some point in their lives, with substantial disability and socioeconomic consequences. Remarkably, around 40% of all LBP cases are attributable to intervertebral disc degeneration (IVDD), a condition that unfortunately lacks a definitive cure. Hence, there is a dire need for innovative therapeutics that not only offer symptomatic relief but also has the capacity to stop or even reverse the IVDD process.The past decade has witnessed an increased interest in harnessing RNA interference (RNAi) mechanisms for therapeutic applications, going all the way to the clinic and meeting the regulatory agencies’ criteria. Given the accumulating evidence that multiple micro-RNAs (miRs) are dysregulated during disc degeneration, they could have a huge potential as biomarkers, targets, or active principles against this debilitating condition. Our miR of choice, miR-155, is downregulated in IVDD and is known to be involved in protecting the IVD from apoptosis, decreasing degradation and controlling inflammation [1]. However, miRNA delivery encounters extracellular and intracellular barriers. Extracellularly, they would be rapidly degraded by endogenous nucleases and intracellularly, their uptake will be hindered by their relatively high molecular weight and negative charge. A promising technique to address this challenge is the vectorization of miRNAs within lipid nanocapsules (LNCs), providing both protection from degradation and improving their uptake within the scarce target cells, called nucleus pulposus (NP), of the degenerated IVD [1,2]. Henceforth, in this study, we developed miR-155 loaded LNCs to be safely injected for the treatment of IVDD. These LNCs were formulated using the phase inversion process by adding cooled miR-155-lipoplexes in the phase inversion zone (PIZ) of a mixture of caprylic-capric triglycerides and hydroxy-stearate-PEG. The LNCs were fully characterized to be 78 nm in hydrodynamic diameter, 0.08 of polydispersity index and +11 mV in zeta potential. Finally, surface modification of the LNCs with targeting peptides was proposed. Nucleus pulposus (NP) cell affinity peptides such as short Link-N (s-Link-N) peptide have a direct anabolic effect on the NP cells and could be utilized in LNCs surface decoration either covalently or by adsorption techniques. Loading the LNCs with both miR-155 and s-Link-N could offer a huge potential in terms of synergetic pro-regenerative effects with enhanced ability to target the NP cells in situ and in vivo. References [1] Clouet, J (2019). Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. Advanced Drug Delivery Reviews [2] Le Moal, B (2022). Lipid nanocapsules for intracellular delivery of microRNA: A first step towards intervertebral disc degeneration therapy. International Journal of Pharmaceutics.