Collagenase-mediated extracellular matrix targeting for enhanced drug penetration and therapeutic efficacy in nanoscale delivery systems for cancer therapy

The highly fibrotic extracellular matrix (ECM) constitutes a major barrier that restricts the penetration and delivery efficiency of anticancer drugs, particularly in fibrotic tumors such as pancreatic cancer, in which cancer-associated fibroblasts (CAFs) secrete excess collagen and cross-linking enzymes to establish a mechanically resistant and poorly compressible tumor microenvironment (TME). This review summarized the pathological mechanisms underlying collagen enrichment in the ECM and its pivotal role in tumor drug resistance, with a systematic overview on recent advances in collagenase-based anticancer therapies, especially those incorporated nano-carrier targeted drug delivery technology. Such approaches degrade the ECM collagen barrier, reducing interstitial pressure and collagen density, thereby substantially improving drug penetration and distribution in TME. Moreover, nano-carrier-mediated collagenase delivery not only circumvents the off-target toxicity associated with systemic administration but also facilitates precise local release and microenvironmental modulation, significantly enhancing the efficacy of other therapies. Critically, this review uniquely differentiates itself from existing literature by providing a comprehensive and comparative evaluation of the burgeoning landscape of nanocarriers specifically engineered for collagenase delivery. We meticulously categorize, analyze, and tabulate diverse nanocarrier platforms (e.g., liposomes, polymeric nanoparticles, micelles, inorganic nanoparticles, hydrogel​) employed in this context over recent years. Their demonstrated efficacy in overcoming the ECM barrier and enhancing subsequent therapeutic outcomes in preclinical models of fibrotic cancers. To our knowledge, this work represents the first dedicated and systematic review within the past five years that consolidates and critically contrasts this rapidly evolving array of nanotechnological approaches for collagenase delivery aimed at ECM modulation. As an emerging synergistic treatment strategy, nano-carrier targeted collagenase delivery exhibits remarkable translational potential as an adjuvant therapy in the treatment of cancer.