Implications for Nanoparticle Identity, Pharmacokinetics, and Organ Targeting—with Reinterpretation of Macrophage-Mediated Translocation as aCorona-Directed Outcome “The body doesn’t see particles. It sees proteins.” Abstract When a nanoparticle is injected intramuscularly, its biological fate is not determined by its chemical compositionalone. From the moment it contacts interstitial fluid, proteins begin adsorbing onto its surface, conferring abiological identity that dictates how the body responds to it. This identity is not fixed: it evolves as the particlemoves through successive biological compartments. The interstitial fluid of muscle tissue generates a first coronadominated by extracellular matrix proteins and opsonins, directing the majority of particles towardmacrophage-mediated uptake — the pathway documented by Gherardi and colleagues. A fraction of particlesescapes to the vascular compartment, where a second, qualitatively different corona forms. Albumin arrives first,conferring transient stealth. Progressive displacement by apolipoproteins converts the particle into a lipoproteinmimetic, enabling LDL receptor-mediated entry into cells not specialized for particulate processing. In thesenon-phagocytic cells, poorly degradable material may generate lysosomal stress, oxidative imbalance, andexposure of intracellular structures normally sequestered from immune recognition. This perspective argues thatmacrophage-mediated translocation is not an anomalous or pathological outcome but the predictable consequenceof the interstitial corona; that the plasma corona generates three distinct biological identities whose relativeprobability is governed by individual apolipoprotein profiles; and that the intracellular consequences ofapolipoprotein-mediated entry into non-phagocytic cells represent an undercharacterized mechanism linkingnanoparticle pharmacokinetics to downstream immune activation.
Añaños et al. (2026) studied this question.