Manganese Dioxide-Entrapping Dendrimers Co-Deliver Protein and Nucleotide for Magnetic Resonance Imaging-Guided Chemodynamic/Starvation/Immune Therapy of Tumors

Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO₂)-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) (<i>m</i>PEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesized and then entrapped with MnO₂ nanoparticles (NPs) to generate the hybrid MnO₂@G5-<i>m</i>PEG–PBA (MGPP) NPs. The created MGPP NPs with an MnO₂ core size of 2.8 nm display efficient glutathione depletion ability, and a favorable Mn²⁺ release profile under a tumor microenvironment mimetic condition to enable Fenton-like reaction and <i>T</i>_<i>1</i>-weighted magnetic resonance (MR) imaging. We show that the MGPP-mediated GOx delivery facilitates enhanced chemodynamic/starvation therapy of cancer cells in vitro, and further codelivery of cGAMP can effectively trigger immunogenic cell death (ICD) to strongly promote the maturation of dendritic cells. In a bilateral mouse colorectal tumor model, the dendrimer delivery nanosystem elicits a potent antitumor performance with a strong abscopal effect, greatly improving the overall mouse survival rate. Importantly, the dendrimer-mediated codelivery not only allows the coordination of Mn²⁺ with GOx and cGAMP for respective chemodynamic/starvation-triggered ICD and augmented STING activation to boost systemic antitumor immune responses, but also enables <i>T</i>₁-weighted tumor MR imaging, potentially serving as a promising nanoplatform for enhanced antitumor therapy with desired immune responses.