Targeting a Moving Threshold: Antigen Density as a Design Constraint for Particulate Drug Delivery in HER2-Low and HER2-Ultralow Breast Cancer—A Narrative Review

Trastuzumab deruxtecan has made breast tumours with minimal HER2 expression therapeutically actionable, and the descriptors HER2-low and HER2-ultralow now carry regulatory weight. Both were defined by immunohistochemical convention and trial eligibility rather than by calibrated measurement. For a receptor-directed particulate carrier the operative question is not whether HER2 is detectable, but whether enough surface-accessible receptor is present, and suitably distributed, to sustain multivalent attachment, clustering, internalisation and payload transfer. This narrative review asks whether principles established in HER2-overexpressing models, in non-HER2 receptor systems and on synthetic interfaces can defensibly be extrapolated to the HER2-low setting, keeping those evidence classes distinct. Antigen density acts at several stages of the delivery cascade rather than at binding alone, jointly with carrier design and tumour transport. An analytical constraint compounds this: fixed-tissue methods report tissue HER2 abundance but do not selectively quantify the accessible receptor pool a carrier can engage. Within the literature identified, no engagement threshold generalisable across platforms was found; the single measured value belongs to one liposomal system studied in vitro. Lesion-level carrier deposition varied widely in both human imaging datasets identified, which illustrate transport heterogeneity but are not comparable. Targetability is platform-specific, and should be measured rather than inferred from categorical HER2 status. No validated model links receptor abundance, ligand density, avidity and internalisation to biological response, so the framework offered is operational.