Enhanced Tumor Site Accumulation and Therapeutic Efficacy of Extracellular Matrix‐Drug Conjugates Targeting Tumor Cells

Abstract The extracellular matrix (ECM) engages in regulatory interactions with cell surface receptors through its constituent proteins and polysaccharides. Therefore, nano‐sized extracellular matrix conjugated with doxorubicin (DOX) is utilized to produce extracellular matrix‐drug conjugates (ECM‐DOX) tailored for targeted delivery to cancer cells. The ECM‐DOX nanoparticles exhibit rod‐like morphology, boasting a commendable drug loading capacity of 4.58%, coupled with acid‐sensitive drug release characteristics. Notably, ECM‐DOX nanoparticles enhance the uptake by tumor cells and possess the ability to penetrate endothelial cells and infiltrate tumor multicellular spheroids. Mechanistic insights reveal that the internalization of ECM‐DOX nanoparticle is facilitated through clathrin‐mediated endocytosis and macropinocytosis, intricately involving hyaluronic acid receptors and integrins. Pharmacokinetic assessments unveil a prolonged blood half‐life of ECM‐DOX nanoparticles at 3.65 h, a substantial improvement over the 1.09 h observed for free DOX. A sustained accumulation effect of ECM‐DOX nanoparticles at tumor sites, with drug levels in tumor tissues surpassing those of free DOX by several‐fold. The profound therapeutic impact of ECM‐DOX nanoparticles is evident in their notable inhibition of tumor growth, extension of median survival time in animals, and significant reduction in DOX‐induced cardiotoxicity. The ECM platform emerges as a promising carrier for avant‐garde nanomedicines in the realm of cancer treatment.