Orchestrating Tumor‐Immune Interface and Microenvironment Remodeling via a Tumor‐Preferential DNA Nano‐Regulator for Metabolic‐Immunotherapy

Metabolic reprogramming in malignant cells drives tumor progression and impairs immunotherapy efficacy, highlighting the urgent need for synergistic metabolic‐immunotherapy. However, the pharmacokinetic disparity and systemic toxicities pose significant challenges on this synergy. We develop a tumor‐preferential, multifunctional DNA nano‐regulator assembled on a DNA origami‐based framework with two functional layers for the integration of immune cues and metabolic modulation at the tumor‐immune interface. The inner layer is precisely functionalized with anti‐CD3/CD28/PD‐L1 antibodies and glutamine synthetase, enabling in situ T‐cell engagement, PD‐L1 blockade, and metabolic environment improvement. The outer layer combines albumin‐binding domains with pH‐responsive i‐motif switches to form a pH‐sensitive albumin coating in vivo, which shields the inner antibodies during systemic circulation and specifically exposes them within the tumoral acidic microenvironment. In the xenograft and syngeneic mouse models, the regulator‐mediated broad remodeling of the intratumoral immune and metabolic landscapes results in enhanced T‑cell infiltration and activation, potent tumor‐growth suppression, and a favorable safety profile. This study combines metabolic intervention with immunotherapy by integrating the synergism and tumor preference of therapies.