Dendronized Polymer‐Derived Nanomedicines for Mitochondrial Dynamics Regulation and Immune Modulation

The effects of dendron side chains in polymeric conjugates on tumor penetration and antigen presentation are systematically examined. Three polymer‐gemcitabine (Gem) conjugates (pG0‐Gem, pG1‐Gem, pG2‐Gem) are designed and prepared. The pG2‐Gem conjugate uniquely binds to the mitochondria of tumor cells, thus regulating mitochondrial dynamics. The interaction between the pG2‐Gem conjugate and the mitochondria promotes great penetration and accumulation of the conjugate at the tumor site, resulting in pronounced antitumor effects in an animal model. Such encouraging therapeutic effects can be ascribed to immune modulation since MHC‐1 antigen presentation is significantly enhanced due to mitochondrial fusion and mitochondrial metabolism alteration after pG2‐Gem treatment. Crucially, the drug‐free dendronized polymer, pG2, is identified to regulate mitochondrial dynamics, and the regulation is independent of the conjugated Gem. Furthermore, the combination of pG2‐Gem with anti‐PD‐1 antibody results in a remarkable tumor clearance rate of 87.5% and a prolonged survival rate of over 150 days, demonstrating the potential of dendronized polymers as an innovative nanoplatform for metabolic modulation and synergistic tumor immunotherapy. This study introduces an innovative dendronized polymer‐derived nanomedicine for breast cancer treatment. Dendron(G2)‐dendronized polymeric conjugate effectively targets tumors to release chemotherapeutic agents, and actively modulates mitochondrial dynamics. This modulation promotes mitochondrial fusion and enhances MHC‐1 antigen presentation, which aids in the activation of cytotoxic T cells, providing a potent, synergistic approach with PD‐1 inhibitor to effectively combat tumors.