B7-H3 (CD276)-DIRECTED SUPRAMOLECULAR NANOPLATFORMS: CONVERGING IMMUNO-TARGETING, SMART RELEASE, AND STROMAL DEPLETION FOR PANCREATIC CANCER THERAPY

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most treatment-resistant solid malignancies. Its poor therapeutic response is caused not only by genetically heterogeneous cancer cells but also by a hypovascular, fibrotic, immunosuppressive tumour microenvironment that restricts drug penetration and weakens antitumour immunity. B7-H3, also known as CD276, has emerged as a biologically relevant surface molecule in PDAC. Human tissue studies show frequent tumour-associated expression, whereas experimental studies link CD276 to invasion, metastasis, apoptosis resistance and reduced gemcitabine sensitivity. These observations provide a rationale for using CD276 as an active address for drug delivery, but expression prevalence and prognostic associations vary across cohorts and assays. Supramolecular nanoplatforms offer a way to combine several functions within one formulation. Non-covalent drug assembly can improve loading of hydrophilic cytotoxics; ligand decoration can increase cell-associated uptake; and pH-, redox- or enzyme-responsive chemistry can delay release until a tumoural or intracellular trigger is encountered. In PDAC, the most direct evidence currently comes from a 2025 preclinical CD276-scFv-modified, pH-responsive liposome containing a copper(II)-gemcitabine supramolecular assembly. The platform improved uptake, pharmacokinetic exposure, short-term xenograft suppression and selected stromal/vascular surrogate markers compared with free gemcitabine and an untargeted formulation. However, this is a single, small, short-duration, immunodeficient study and does not establish clinical efficacy or immune remodelling. This review synthesises the biological rationale for CD276-directed delivery, the design principles of supramolecular nanoplatforms, the opportunities and risks of combining immuno-targeting with smart release and stromal modulation, and the preclinical evidence required for translation. The central conclusion is that CD276-directed supramolecular delivery is a promising PDAC strategy, but it should currently be described as a preclinical proof of concept rather than a clinically validated therapy.