Overcoming the p-EMT-mediated stromal barrier at the tumor periphery with hybrid membrane-camouflaged nanoplatform for enhanced chemotherapy

Abstract

Effective intratumoral penetration of nanotherapeutics is the prerequisite for successful cancer treatment. However, the dense tumor stroma often hinders deep drug penetration. In this work, we identified a previously overlooked physiological barrier at the leading edge of tumor nests, which was formed by the tumor cells undergoing partial epithelial-mesenchymal transformation (p-EMT). Adjacent cancer-associated fibroblasts (CAFs) promote this process through paracrine signaling, ultimately blocking nanoparticle penetration into the tumor interstitium. In light of this, we elaborately developed a tailored nanodrug, C/D-MOF_HM, by camouflaging a curcumin (CUR)-based, doxorubicin (DOX)-loaded, metal-organic framework nanoparticle with a hybrid membrane derived from CAFs and tumor cells. The C/D-MOF_HM selectively deliveres CUR to CAFs to inhibit the secretion of p-EMT-inducing factors (e.g., TGF-β1 and IL-6), thereby suppressing p-EMT-mediated stromal matrix formation at the tumor periphery. As a result, augmented drug penetration of C/D-MOF_HM is evidently observed, leading to potent tumor growth inhibition and metastasis suppression. This p-EMT blockade strategy for diminishing the stromal barrier at tumor margins represents a feasible approach to improve drug penetration into solid tumors for enhanced tumor therapy.