A Self‐Propelled DNA‐Based Nanorobot for Hypoxic Tumor Therapy

ABSTRACT Solid tumors pose major therapeutic hurdles due to pathophysiological barriers such as hypoxia and dense stroma, which severely restrict drug penetration. Conventional nanomedicines lack the autonomous capability to navigate these evolving obstacles. Here, we engineer a DNA‑based nanorobot constructed on an optimized tetrahedral framework nucleic acid (tFNA) that co‑assembles tumor‑targeting aptamers, catalytic platinum nanoparticles (Pt‑NPs), and the therapeutic payload methylene blue (MB) into a single modular platform. This integrated design enables three coordinated functions: tumor‑specific recognition, self‑propelled transport driven by oxygen generation, and concurrent hypoxia alleviation to potentiate photodynamic therapy (PDT) in hypoxic tumors. The Pt‐NPs catalyze the decomposition of overproduced hydrogen peroxide (H 2 O 2 ) in the tumor microenvironment, generating oxygen bubbles that both drive deep tissue penetration (to depths > 300 µm) and alleviate local hypoxia. This self‑powered propulsion enables efficient delivery of MB, leading to cascaded PDT activation. In vivo, the nanorobot achieves 85% tumor regression through the coordinated actions of deep penetration, hypoxia relief, and enhanced PDT. This modular DNA nanoplatform provides a promising strategy for advanced nanomedicine by autonomously addressing key delivery barriers in solid tumor therapy.