Mechano-metabOlic Responsive nanoPlatform for HeterogEnous tUmor Suppression

Objetivo

Therapy-resistant solid tumors, sustained by the interplay of extracellular matrix (ECM) stiffening and metabolic plasticity of cancer stem cells (CSCs), remain among the most intractable problems in oncology. In cholangiocarcinoma (CCA), these mechano–metabolic adaptations converge as dense fibrotic stroma, mitochondrial hyperactivity, glycolytic reprogramming, and immune exclusion—together blocking therapy penetration and driving recurrence. No existing treatment integrates ECM mechanics, metabolic rewiring, and mitochondrial targeting into a single, ordered sequence. MORPHEUS is the first nanomedicine to achieve this, executing a rare triple-gate cascade—ECM remodeling, glycolysis disruption, and mitochondrial collapse—within a rigid, C3-functionalised triptycene scaffold. Its architecture enforces geometric orthogonality, kinetic insulation, and scalable synthesis, overcoming the crosstalk and instability of conventional nanocarriers. The cascade initiates with a lactate-sensitive shield that unmasks ECM-modulating agents to soften desmoplastic stroma and enhance immune and drug infiltration. The second gate, triggered by lactyl-CoA or GLO1/GLO2, releases glycolysis-targeting payloads to eradicate glycolytic CSCs. The third gate senses mitochondrial reactive oxygen species (ROS), deploying OXPHOS inhibitors/ROS disruptors to collapse energy production in OXPHOS-dependent CSCs. Integrated companion diagnostics will quantify ECM stiffness, metabolic phenotypes, and CSC composition, enabling patient-tailored configurations. Validation across 3D tumor-mimetic systems, patient-derived organoids, and orthotopic xenografts ensures translational robustness. By reshaping tumor biology to open transient “windows of vulnerability,” MORPHEUS represents a bold high-risk/high-gain paradigm shift, first addressing CCA as an orphan indication and extending as a scalable blueprint for stroma-rich, therapy-refractory cancers.