<p>High-density lipoproteins (HDLs) are endogenous nanoparticles critical for cholesterol transport, vascular protection, and immune modulation. Cardiovascular disease (CVD) often induces dysfunctional HDL, driving the emergence of HDL-mimicking nanoparticles (HMNPs)—engineered particles aiming to restore or enhance biological functions. This review details advances in HMNP design, including theranostic platforms and computational engineering, focusing on recent preclinical and clinical results. Key translational barriers such as manufacturing scale, regulatory complexity, population variability, and imaging agent toxicity are discussed, along with future opportunities in multi-target nanoplatforms and computational optimization. HMNPs show promise for advancing cardiovascular care by combining therapeutic and imaging capabilities, offering new hope for heart disease; however, further research is needed to overcome technical and clinical challenges and validate their real-world impact.</p> Graphical Abstract <p></p>