Coordination of Mechanodynamic Structure and Biochemical Signaling Restores ECM Soft‐Stiff Homeostasis for Anti‐Metastasis Tumor Therapy

Cervical cancer is one of the most common and lethal malignancies in women worldwide, with distant metastasis being the major cause of poor prognosis. Heterogeneous remodeling of the extracellular matrix (ECM) induces a soft‐stiff disequilibrium, excessive stiffening promotes lamellipodia formation and directional migration, whereas MMP‐mediated softening weakens the structural barrier and accelerates tumor dissemination. This bidirectional disequilibrium indicates that restoring ECM mechanical homeostasis, rather than simply altering stiffness, is crucial for effective antitumor therapy. Here, novel hyperbranched cyclodextrin‐based nanoparticles (DNPt/12K‐β‐CD) were developed to synergistically regulate ECM soft‐stiff disequilibrium. Upon exposure to the reductive tumor microenvironment, the nanoparticles dissociates, and DNPt(IV) is reduced to release 2‐(6‐methoxynaphthalen‐2‐yl) acetic acid (DN) and oxaliplatin (OXa). DN inhibits the COX‐2/PGE2‐MMP axis to prevent barrier degradation and angiogenesis, while OXa induces apoptosis to suppress tumor growth. The hyperbranched cyclodextrin (12K‐β‐CD) forms a 3D multi‐cavity cooperative framework that functions as a “molecular fleet,” extracts cholesterol from lipid rafts, disrupting their integrity, and inhibits the formation of lamellipodia. This system functionally restores ECM soft‐stiff homeostasis, through coordinated regulation of mechanodynamic structure and biochemical signaling, providing a new therapeutic strategy for cervical cancer and other malignancies related to ECM remodeling.