Excipient-Mediated Vectorisation Across Biological Barriers: The Vascular Escape–Corona–Transcytosis (VECT) Model of Iatrogenic Disease

Abstract

Abstract Background Biological barriers are selectively permeable interfaces whose receptor-mediated transport systems create a structural vulnerability: receptors recognise ligands on the exterior of approaching complexes and initiate transcytosis without evaluating the full internal composition of the supramolecular structure bearing those signatures. This vulnerability is already exploited by microbial pathogens through evolved receptor engagement and Trojan-horse mechanisms [1], and deliberately by drug-delivery systems that coat particles with apolipoprotein-recruiting surfactants to achieve blood-brain barrier crossing [2,3]. The present paper asks whether parenteral pharmaceutical formulations containing interface-organising excipients may inadvertently generate a related phenomenon. Hypothesis The Vascular Escape–Corona–Transcytosis (VECT) model proposes that a subset of immune-mediated and inflammatory adverse events associated with parenteral administration of excipient-containing biologics arises from a four-link causal chain: (1) vascular access of the formulated complex; (2) formation of a plasma protein corona organised by the polyethoxylated excipient interface, enriched in apolipoprotein E, complement, or IgG depending on complex architecture; (3) corona-dependent, receptor mediated transcytosis across barrier endothelia expressing LRP1, megalin/LRP2, FcRn [4], SR-B1, integrin αvβ3, or complement receptors CR1/CR3; and (4) local immune activation in the exposed compartment, producing a phenotype determined by which barrier was crossed. Within the broader family of polyethoxylated excipients — polysorbates, PEG-lipids, Cremophor EL, poloxamers — polysorbates are the best-characterised and most prevalent case, and constitute the primary focus of the mechanistic framework developed here. Evidence base This paper synthesises nine prior publications in the series Compartmental Autoimmunity: Convergent Pathways (Zenodo, 2026), each of which established one mechanistic fragment: apolipoprotein-mediated BBB transcytosis of aluminium adjuvant nanoparticles [5]; sorbitol as an excipient-class barrier disruptor [6]; triple MMP-9 convergence in neonatal BBB vulnerability [7]; interstitial-to-plasma corona remodelling as the basis of route-dependent risk [8]; PS80 as a vectorising excipient for residual DNA in anti-TNF biologics [9]; theGardasil/Cervarix natural experiment demonstrating architecture-dependent POI and POTS signals [10]; the double dissociation between PEG-LNP myocarditis and PS80-associated POI/POTS confirming architecture as the independent variable [11]; PS20 (polysorbate 20, a shorter-chain polysorbate) as the initiator of Engerix-B demyelination without invoking molecular mimicry [12]; and aluminium adjuvants, PS80, and gram-negative bacteria as potential co-initiators of organ-specific autoimmunity [30]. The EMA’s 2023 guideline on polysorbates establishes that polysorbate-mediated enhancement of brain uptake is a recognised biological property under defined conditions, warranting consideration in benefit-risk evaluation [13]. The VECT model extends this acknowledgement to a broader receptor landscape, additional barriers, and cumulative exposure contexts. Conclusions The VECT model should not be read as a claim that polysorbates or related excipients are intrinsically toxic, nor that every formulation containing them carries clinically meaningful barrier-crossing risk. Its claim is narrower and more testable: under conditions of vascular access, permissive plasma corona formation, receptor engagement and local immune susceptibility, an excipient-organised pharmaceutical complex may exploit the same receptor-mediated transport logic that biological barriers use for physiological cargoes, that pathogens may hijack during infection, and that drug-delivery systems deliberately engineer for therapeutic purposes. Because completion of this chain requires the coincidence of several independently low-probability conditions, the events it describes are predicted to remain rare — rarity is a structural feature of the model, not an exception to it. If this hypothesis is correct, rare immune-mediated adverse events should not be analysed only by antigen, therapeutic target or active ingredient; they should also be stratified by excipient architecture, corona composition, route of administration, receptor biology and cumulative exposure. If it is wrong, it should fail in direct corona-comparison assays, receptor-blocking transcytosis experiments and excipient-stratified pharmacovigilance analyses. The value of VECT lies not in asserting causality, but in making a previously invisible variable experimentally visible.