Harnessing nanomedicine to target NF-κB signalling in cancer: at the intersection of inflammatory signalling, metabolic reprogramming, and therapeutic innovation

Abstract The nuclear factor kappa B (NF-κB) signalling pathway is a pivotal orchestrator of inflammation, tumour progression, immune modulation, and metabolic reprogramming within the dynamic landscape of the tumour microenvironment (TME). Aberrant and sustained activation of NF-κB is frequently associated with tumour proliferation, resistance to therapy, and poor clinical outcomes. However, conventional NF-κB inhibitors face significant limitations, including systemic toxicity, poor bioavailability, and lack of tumour specificity. Nanomedicine offers a transformative approach to overcome these barriers by enabling the targeted delivery of NF-κB modulators, such as small molecules, RNA interference agents, and gene-editing systems, directly to tumour sites. Recent advances in nanocarriers, including liposomes, polymeric nanoparticles, exosomes, and dendrimers, have demonstrated improved therapeutic indices, enhanced stability, and reduced off-target effects. This review highlights the convergence of nanotechnology, inflammatory signalling, and cancer metabolism, with a focus on how nanomedicine can precisely modulate NF-κB signalling to reprogramme tumour-associated macrophages and remodel the TME. It also discusses preclinical evidence supporting NF-κB-targeted nanomedicine, innovative delivery strategies, and the translational challenges that impede clinical adoption. Collectively, these insights highlight the potential of nanomedicine in advancing NF-κB-targeted cancer therapy by enhancing drug specificity, safety, and therapeutic responsiveness. Future developments integrating artificial intelligence, theranostic design, and personalised nanomedicine are expected to accelerate clinical translation and establish NF-κB-targeted nanotherapeutics as a cornerstone of next-generation precision oncology. Graphical Abstract