FAK Mediated Coordination of Extracellular Matrix Remodeling and Cellular Mechanics Impairs Nanomedicine Delivery in Solid Tumors

Abstract

ABSTRACT Tumor extracellular matrix (ECM) remodeling and cell‐intrinsic mechanical properties critically limit nanoparticle (NP) delivery, yet how these multiscale biophysical cues are coordinately regulated remains unclear. Here, we identify focal adhesion kinase (FAK/ PTK2 ) as a central mechanobiological regulator that couples ECM remodeling with cellular mechanics to control NP transport and cellular uptake. The ECM derived from patients' tumors exhibited increased stiffness and collagen density, which severely restricted NP penetration, while PTK2 emerged as a key integrin‐associated signaling hub linked to ECM organization. FAK depletion or inhibition disrupted ECM homeostasis, significantly enhanced NP penetration and cellular uptake. Mechanistically, FAK loss reduced cellular stiffness and cytoskeletal tension while increasing membrane deformability and transcriptionally reprogramming endocytic pathways, with clathrin‐mediated endocytosis as the dominant route. In vivo, FAK ablation remodeled the tumor stroma to enhance NP accumulation and penetration, and the combination of FAK inhibition with chemotherapy demonstrated potent antitumor efficacy. Together, these results establish a multiscale mechanistic paradigm in which FAK integrates ECM biophysics, cellular mechanics, and endocytic regulation to gatekeep nanomedicine delivery. Targeting FAK offers a potential strategy to enhance therapeutic penetration and efficacy in solid tumors.