Lower back pain is a global epidemiological and socioeconomic problem. Biomaterial and cell-based therapies have been pursued for the treatment of degenerated intervertebral disc (IVD), with a number of clinical trials underway. However, the degenerated intervertebral disc has a distinct environment (e.g. altered oxygen, glucose, acidity, inflammatory cytokine levels) that is unique to an individual (i.e. patient-specific) and will ultimately determine the likelihood and rate at which regeneration can occur. A “one size fits all” approach will lead to the failure to demonstrate efficacy of advanced therapies, as they are not being designed or personalised for individual patients. This proposal envisions a future whereby advanced gene activated cell therapies are personalised (targeting regeneration or modulating inflammation) to treat back pain based on knowing the individuals unique disc microenvironment. This will be achieved through profiling of individual patient disc microenvironmental factors, with in vitro screening and in silico modelling to design cell therapies and predict regeneration outcomes (Aim 1) combined with the development of tailored functionalised gene activated biomaterials (Aim 2), to enhance matrix formation and modulate the inflammatory processes (Aim 3). Gene-based therapy offers several advantages over direct delivery of proteins or small molecules, among them the possibility of sustained efficacy and endogenous synthesis of growth factors or suppression of inflammatory factors and pathways. The platform technology (personalised gene activated biomaterials to regulate regeneration and inflammation) and knowledge (tailoring cell therapies to suit patient-specific microenvironments) generated through this research are beyond the current state-of-the-art and will provide a significant transformative scientific and clinical step change opening new horizons in minimally-invasive therapeutic strategies.