From Inflammation to Targeted Therapy: Leveraging Neutrophil, Platelet, RBC, and Macrophage Biology for Nanocarrier in Atherosclerosis

Purpose of Review: Cell hitchhiking harnesses endogenous circulating cells as programmable carriers to achieve precise, lesion-targeted nanotherapeutic delivery in atherosclerosis. This review examines the mechanistic basis and translational strategies of neutrophil-, platelet-, macrophage-, and red blood cell–based systems, emphasizing their potential to convert the plaque microenvironment from a therapeutic barrier into a receptive target. Recent Findings: Hitchhiking modalities—including surface anchoring, internalization, and membrane cloaking—exploit innate trafficking cues and pathophysiologic triggers such as oxidative stress, matrix metalloproteases, acidic pH, and shear stress to achieve site-specific payload release. Preclinical studies in ApoE⁻/⁻ and large-animal models demonstrate enhanced plaque accumulation, reduced lipid burden, and improved stability using neutrophil-ferried ROS scavengers, platelet-mimetic rapamycin carriers, and macrophage-anchored lipid modulators. These biohybrid platforms benefit from prolonged circulation via CD47-mediated immune evasion and are compatible with PET/MRI theranostics. Summary: Hitchhiking strategies address the limitations of conventional nanotherapies by combining active targeting, prolonged bioavailability, and localized release, yet translation faces challenges including off-target immune activation, thrombogenicity, donor variability, and manufacturing hurdles. Standardized preclinical comparisons, rigorous hemocompatibility testing, imaging-guided trials, and hybrid dual-responsive carriers may optimize efficacy and safety. By integrating cellular biology with nanomaterial engineering and regulatory considerations, cell hitchhiking represents a precision approach for durable plaque stabilization and reduced cardiovascular risk.