Engineering ECM-Responsive Nanomedicine to Overcome Tumor Stromal Barriers

Abstract

Tumor stromal barriers remain a major obstacle to the clinical efficacy of nanomedicine in solid tumors, with the extracellular matrix (ECM) governing nanoparticle transport, drug distribution, and therapeutic accessibility within the tumor microenvironment. Excessive collagen deposition, hyaluronic acid accumulation, elevated interstitial fluid pressure, and remodeling by cancer-associated fibroblasts generate a dense stromal architecture that limits uniform intratumoral penetration of nanoscale therapeutics. Consequently, many nanocarrier systems, despite optimized pharmacokinetic properties, fail to achieve effective drug delivery beyond perivascular tumor regions. Recent advances in materials engineering have enabled the development of ECM-responsive nanomedicine platforms that integrate ECM-targeting ligands, protease-responsive activation mechanisms, stromal remodeling strategies, and physically adaptive carrier architectures to overcome tumor stromal barriers. These approaches transform the ECM from a transport barrier into a programmable therapeutic interface, enabling selective activation, enhanced stromal penetration, and spatially controlled drug release. In parallel, enzyme-mediated stromal remodeling and cancer-associated fibroblast reprogramming have emerged as complementary strategies for restoring interstitial transport and improving intratumoral drug distribution. This review summarizes recent progress in engineering ECM-responsive nanomedicine to overcome tumor stromal barriers, with emphasis on ECM-targeted delivery, protease-responsive nanomedicine, enzyme-mediated matrix remodeling, physically adaptive nanocarriers, and ECM-guided immunomodulatory strategies. Emerging spatial omics technologies and ECM-mimetic modeling platforms are also discussed as enabling tools for the rational design of next-generation delivery systems. Collectively, these advances support a transition from passive accumulation-based delivery toward programmable stromal interface engineering for more effective cancer nanomedicine.