Nanomedicine based on collagenase penetration for tumor immunotherapy induced by low-dose chemotherapy

Despite extensive research on functional nanomaterials for antitumor applications, their efficacy remains limited by the complex tumor microenvironment (TME). Dense extracellular matrix (ECM) and aberrant vasculature impede nanoparticle penetration into solid tumors, reducing treatment efficacy in deep-seated regions. This study developed a collagenase-IV (COL)-based nanomedicine (COL/DTX@BSA NPs) to address the limited penetration of nanodrugs into deep solid tumors caused by the dense extracellular matrix (ECM). By co-encapsulating COL and the chemotherapeutic agent docetaxel (DTX) into bovine serum albumin (BSA) nanoparticles, an "enzyme-enhanced penetration" strategy combined with chemo-immunotherapy synergy was achieved. Upon release in the tumor microenvironment, COL acts as "molecular scissors" to degrade collagen fibers in the ECM, significantly enhancing the deep tumor penetration of both the nanoparticles and the drug.The research demonstrated that DTX not only induces chemotherapy-mediated cytotoxicity but also triggers immunogenic cell death (ICD), promoting the release of damage-associated molecular patterns such as calreticulin, ATP, and high-mobility group protein B1, thereby activating an anti-tumor immune response. The COL-mediated penetration strategy enables low-dose DTX to effectively induce ICD in deep tumor regions, resulting in a synergistic effect between chemotherapy and immunotherapy. This work provides a new reference for collagenase-based drug delivery strategies targeting deep tumors and expands the application prospects of low-dose chemotherapy-induced ICD in nanomedicine.