Tri-component programmable nanoregulator with Three-pronged penetration boosts immunotherapy of Triple-Negative breast cancer

Cancer associated fibroblasts (CAFs) are crucial stromal cells in desmoplastic triple-negative breast cancer (TNBC) inducing abundant extracellular matrix (ECM), resulting in the poor penetration of therapeutic drugs and immunosuppressive tumor microenvironment (TME). Here, a safe and green nanoregulator ORM based on oleanolic acid (OA) nanogel incorporating sonosensitizer rose bengal (RB) and photothermal agent methylene blue (MB) with three-pronged deep intratumoral penetration and TME modulation was fabricated to improve therapies of TNBC. The inactivation of CAFs by deformable OA nanogel allows ORM enter into cancer cells more easily. The following light irradiation not only decomoposes MB to exert photothermal therapy (PTT) to degrade collagen and remodel the ECM for improved penetration, but also triggers the RB release. Finally, the ultrasound further promotes the deep penetration of RB to achieve sonodynamic therapy (SDT). ORM with programmable PTT and SDT reshapes tumor immune microenvironment and boosts anti-PD-L1-mediated immunotherapy, leading to remarkable inhibition of the growth of primary and distant tumors and protection against tumor rechallenge. The present three-pronged penetration and programmable regulation approach by a nanoregulator composed of clinically-applied agents provide a promising pathway to design clinically transformable nanomedicine for effective combination therapy of TNBC.