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Diabetes mellitus presents complex constellation of multiple long-term conditions (MLTCs) including cardiovascular, renal, metabolic, and neuroinflammatory disorders. This leads to clinical heterogeneity, polypharmacy, therapeutic disinterest, adverse outcomes, societal challenges, and glycaemic control management strategies. Precision medicine-based approach address this intricacy through alignment of therapeutic interventions with consideration of biological profiles. In this, nanogenomic synergy is a breakthrough, that gives detailed insight of genomic and epigenomics in context to advanced nanotechnology-based drug delivery system for personalized diabetes care. Genomics and transcriptomic profiling approach stratified the patients based on molecular drivers of diabetes and treatment responses, whilst nanotechnology facilitated the targeted, controlled and tissue specific systemic effect with minimal toxicity and off-target effects. This mini review will present the current evidence and understanding of clinical and biological obstacles in management of MLTC associated with diabetes mellitus and investigate the role of nano genomics through shard pathogenic pathways across comorbid conditions. Many key evidence nanotechnology platforms for genomic guidance in therapeutics were also covered. A nanogenomic synergy is a very innovative concept that could potentially break through one-size-fits-all approaches by allowing the redefinition of diabetic care for people living with multiple long-term diseases. This is achieved through precision, innovation, and a more encompassing approach to care.