Extracellular matrix modulating enzyme functionalized biomimetic Au nanoplatform-mediated enhanced tumor penetration and synergistic antitumor therapy for pancreatic cancer.

Abstract

Excessive extracellular matrix (ECM) deposition in pancreatic ductal adenocarcinoma (PDAC) severely limits therapeutic drug penetration into tumors and is associated with poor prognosis. Collagen is the most abundant matrix protein in the tumor ECM, which is the main obstacle that severely hinders the diffusion of chemotherapeutic drugs or nanomedicines. We designed a collagenase-functionalized biomimetic drug-loaded Au nanoplatform that combined ECM degradation, active targeting, immune evasion, near-infrared (NIR) light-triggered drug release, and synergistic antitumor therapy and diagnosis into one nanoplatform. PDAC tumor cell membranes were extracted and coated onto doxorubicin (Dox)-loaded Au nanocages, and then collagenase was added to functionalize the cell membrane through lipid insertion. We evaluated the physicochemical properties, in vitro and in vivo targeting, penetration and therapeutic efficacy of the nanoplatform. Upon intravenous injection, this nanoplatform efficiently targeted the tumor through the homologous targeting properties of the coated cell membrane. During penetration into the tumor tissue, the dense ECM in the PDAC tissues was gradually degraded by collagenase, leading to a looser ECM structure and deep penetration within the tumor parenchyma. Under NIR irradiation, both photothermal and photodynamic effects were produced and the encapsulated chemotherapeutic drugs were released effectively, exerting a strong synergistic antitumor effect. Moreover, this nanoplatform has X-ray attenuation properties that could serve to guide and monitor treatment by CT imaging. This work presented a unique and facile yet effective strategy to modulate ECM components in PDAC, enhance tumor penetration and tumor-killing effects and provide therapeutic guidance and monitoring.