Dendrimer/Copper(II) Complex-Mediated siRNA Delivery\nDisrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment\nagainst Tumor Growth and Metastasis

Solid\ntumors reprogram metabolic pathways to meet their biosynthesis\ndemands, resulting in elevated levels of metabolites in the tumor\nmicroenvironment (TME), including lactate. Excessive accumulation\nand active transportation of lactate within the TME drives tumor progression,\nmetastasis, and immunosuppression. Interruption of TME lactate metabolism\nis expected to restore antitumor responses and sensitize tumor immunotherapy.\nHerein, we developed phenylboronic acid- and pyridine-modified poly(amidoamine)\ndendrimer/copper(II) (Cu(II)) complexes, namely, D-Cu complexes, to\ndeliver monocarboxylate transporter 4 siRNA (siMCT4) and disrupt the\ntumor lactate shuttle. The D-Cu complexes are shown to have a Cu(II)-mediated\nchemodynamic effect and <i>T</i><sub><i>1</i></sub>-weighted magnetic resonance imaging potential (<i>r</i><sub><i>1</i></sub> relaxivity = 1.19 mM<sup>–1</sup> s<sup>–1</sup>), enabling effective siMCT4 delivery to inhibit\nlactate efflux within cancer cells. In combination with a CD11b immune\nagonist, the treatment of D-Cu/siMCT4 polyplexes in a mouse breast\ntumor model alleviates local TME immunosuppression, leading to excellent\ninhibition of both primary tumor growth and lung metastasis.