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The growing use of nanomaterials (NMs) in consumer, medical and industrial products raises significant concerns about human exposure and the risk of cardiovascular toxicity. This narrative review synthesizes three critical and interconnected aspects of nanomaterial-induced cardiotoxicity-risk assessment models, mechanisms, and mitigation strategies-with the overarching goal of advancing fundamental knowledge and supporting the development of safer NMs. A variety of assessment models are explored, ranging from traditional in vitro and in vivo systems to emerging organ-on-a-chip platforms. A tiered, decision-driven strategy for model selection is based on risk-stage, objective-orientation, evidence complementarity, and ethical optimization, with emphasis on the critical need to assess toxicity under pathological conditions. Key mechanisms include oxidative stress, mitochondrial dysfunction, inflammatory responses, disruption of ion homeostasis, and induction of cell death. The specific pathway is often dictated by the physicochemical properties of nanoparticle. Potential mitigation strategies include surface engineering, elemental substitution/doping, morphological design, the use of chelating agents/antioxidants, and adopting Safe-by-Design principles. Interdisciplinary collaboration is crucial during the developmental phase to balance the immense application potential of NMs with the imperative to address their associated toxicity challenges.