Peptide-guided nanotheranostics engaging the tumor fibrin-fibronectin niche: From CREKA to clinical translation

The tumor microenvironment (TME) impairs drug delivery and immune clearance through aberrant fibrin deposition, dense extracellular matrix and dysfunctional vasculature. Cys-Arg-Glu-Lys-Ala (CREKA), a pentapeptide tumor-homing ligand, binds fibrin-fibronectin complexes overexpressed in the tumor stroma. Unlike conventional peptides targeting cell-surface receptors, which are frequently downregulated in advanced tumors, CREKA engages stable extracellular components, sidestepping receptor-expression heterogeneity and offering greater selectivity than passive delivery alone. This review integrates three threads usually treated separately: the molecular basis of CREKA binding, its self-amplifying tumor accumulation, and the breadth of preclinical delivery and imaging platforms. We examine CREKA conjugated to liposomes, polymeric nanoparticles, iron oxide nanoparticles, carbon nanotubes and siRNA carriers, with reported tumor enrichment of up to about 6-fold over non-targeted controls in individual studies. Incorporated into magnetic resonance imaging (MRI), positron emission tomography (PET) and near-infrared platforms, preclinical CREKA probes have visualized 0.4-0.5 mm metastases, below conventional detection limits. We further assess its electrostatic binding, self-amplification through localized clot formation, and synergy with photothermal, magnetic and immunotherapeutic strategies. Critically, fibrin-fibronectin targets are not tumor-exclusive, a key translational limitation. Together, these findings establish CREKA-based theranostics as a promising preclinical strategy uniting molecular imaging with targeted therapy on one platform.