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

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.