Matrix Metalloproteinase-2-Induced Morphologic Transformation of Self- Assembled Peptide Nanocarriers Inhibits Tumor Growth and Metastasis

Despite the rapid development of novel drug delivery systems, the limited intratumor accumulation of drugs and immunomodulatory function of drug nanovehicles still limit their therapeutic efficiency. Deeper penetration can be achieved by reducing the size of nanocarriers after reaching the tumor site. However, the persistence of such nanocarriers is limited due to their small particle size and ease of removal from tumors. Here, we design a matrix metalloproteinase-2 (MMP-2)-responsive peptide, AGLR, that can encapsulate the chemotherapeutic drug doxorubicin (DOX) and self-assemble to form spherical nanoparticles (NPs) in a physiological environment, which enhances drug penetration in tumor tissue. Upon cleavage by MMP-2 overexpressed in the tumor microenvironment, DOX/AGLR is transformed from spherical NPs to nanofibers (NFs), improving the DOX retention time and accumulation in tumors in vivo. Furthermore, DOX/AGLR penetrates the extracellular matrix (ECM) and inhibited the upregulation of CCL2 and CD31, inhibiting tumor growth and lung metastasis. Importantly, DOX/AGLR increased the proportion of DC cells and decreased the proliferation of Treg cells. The expression of TGF-beta and PD-L1 was downregulated, indicating that DOX/AGLR alleviated the immunosuppressive tumor microenvironment. This enzyme-responsive, morphologically transformable drug -delivery strategy provides a promising general tumor therapy modality with enhanced antitumor efficacy and immunomodulation.