Multivalent Aptamer Assembly Enhances Tumor-Specific Degradation of Transforming Growth Factor-Beta to Remodel the Stromal and Immunosuppressive Cancer Microenvironment

Extracellular proteins like transforming growth factor-β (TGFβ) are crucial enforcers in the development of cancer stroma and the tumor immunosuppressive microenvironment. Lysosome-targeting chimera-mediated protein degradation appeared as a promising tool for extracellular signal interference but was limited by several lysosome-trafficking receptors and inadequate in vivo degradation efficiency. Here, we designed a multivalent aptamer assembly with a universal pattern to drag extracellular proteins (e.g., TGFβ1) for lysosome degradation with high tumor specificity. By accelerating cell recognition-internalization and lysosomal delivery, the assembly promoted TGFβ blockade and degradation in pancreatic cancer cells and pancreatic stellate cells (PSCs). In vivo, the assembly exhibited highly tumor-specific accumulation and prolonged retention, which resulted in efficient TGFβ inhibition, stromal remodeling, and reversed polarization of immunosuppressive cells in the tumor microenvironment, as well as synergic therapeutic effects when combined with gemcitabine or ovalbumin. Therefore, this study provides a feasible strategy to construct a multivalent aptamer assembly for tumor-specific extracellular protein degradation, after remodeling the tumor stromal and immunosuppressive microenvironment in a manner that enhances the effects of cancer chemotherapy and immunotherapy.