Targeted nanocarriers in gastric cancer: a critical review of HER2, CLDN18.2 and EGFR-directed translational evidence

Abstract

Targeted nanocarriers are increasingly proposed to overcome therapeutic resistance and peritoneal recurrence in gastric cancer (GC), yet clinical translation remains limited and, in our reading, systematically over-promised. This review addresses three conflated questions: whether HER2, CLDN18.2, and EGFR function not only as disease targets but as reliable nanocarrier gateways; which delivery barriers are realistically engineerable rather than merely describable; and why preclinical efficacy has rarely advanced to clinical benefit despite a decade of activity. A structured narrative search of PubMed, Web of Science, and Google Scholar identified English-language literature (January 2014–April 2026) on GC nanocarriers, platforms, molecular targeting, trial registries (ClinicalTrials.gov) and translational nanomedicine. From 1,247 records, 186 GC-relevant studies were retained and classified across evidentiary tiers, and re-read for what they omitted—untargeted controls, quantitative biodistribution, orthotopic or peritoneal-metastasis modelling, and molecular-subtype stratification. HER2-directed nanocarriers are constrained by intratumoral heterogeneity and dynamic target loss, with most positive data from uniformly HER2-high cell lines. CLDN18.2 offers stronger specificity but faces assay-dependent prevalence, tight-junction sequestration limiting ligand access, and accelerating antibody-drug conjugate (ADC) competition. EGFR remains exploratory, as antibody failure (EXPAND, REAL3) is unreconciled with nanocarrier reuse and normal-tissue expression imposes a toxicity ceiling. Across platforms, nanoformulation reproducibly improves tolerability but rarely enhances intratumoral delivery, often reflecting solubilizer removal rather than a true “nano-effect”. Progress is further limited by overreliance on subcutaneous xenografts and near-absent integration of subtype, route, and manufacturability. GC nanomedicine should shift from platform enthusiasm to disease-specific translational discipline. Intraperitoneal nanocarriers for peritoneal metastasis carry the highest near-term potential, whereas heterogeneity-ignoring HER2 and ADC-ignoring CLDN18.2 monotherapy programmes, and the emphasis on multi-stimuli-responsive and exosome-based delivery, risk being overstated. Future studies require route-specific design, subtype-guided selection, targeted-versus-untargeted controls, quantitative biodistribution, orthotopic/peritoneal validation, and an agreed minimum translational dataset.