Dual-responsive liposomal nanoplatform integrating MMP-2 inhibition and EV-enhanced intratumoral delivery for synergistic anti-tumor and anti-metastatic therapy

Inhibiting the activity of matrix metalloproteinases (MMPs) to preserve extracellular matrix (ECM) integrity and impede metastasis remains challenging with conventional chemotherapeutics. To address this, we developed liposomal nanoparticles (Lip/Dox/Mon-Pep NPs) for the inhibition of both tumor growth and metastasis. These NPs featured a MMP-2 inhibitory peptide (Pep) on their surface and a core composed of a mixture of acid- and glutathione (GSH)-dual-sensitive lipid, encapsulating Doxorubicin (Dox) and Monensin (Mon). Within the acidic and high-GSH tumor microenvironment, these NPs responsively cleaved amide and disulfide bonds, releasing Pep, Dox, and Mon simultaneously. Pep inhibited MMP-2 activity, preserving ECM integrity and hindering tumor cell migration/invasion; Dox suppressed tumor cell proliferation; while Mon elevated intracellular calcium, promoting tumor-derived extracellular vesicles (EVs) secretion and enhancing Dox delivery. In vivo studies demonstrated favorable tumor targeting, deep penetration, low systemic toxicity, and significant inhibition of both 4T1 breast tumor growth and lung metastasis in mice. This system integrates targeted delivery, enhanced drug penetration, and active ECM protection, providing an effective strategy for combined antitumor and antimetastatic therapy.