A Versatile G‐Quadruplex (G4)‐Coated Upconverted Metal‐Organic Framework for Hypoxic Tumor Therapy

Abstract Given the complexity of the tumor microenvironment, multiple strategies are being explored to tackle hypoxic tumors. The most efficient strategies combine several therapeutic modalities and typically requires the development of multifunctional nanocomposites through sophisticated synthetic procedures. Herein, the G‐quadruplex (G4)‐forming sequence AS1411‐A (d[(G 2 T) 4 TG(TG 2 ) 4 A]) is used for both its anti‐tumor and biocatalytic properties when combined with hemin, increasing the production of O 2 ca. two‐fold as compared to the parent AS1411 sequence. The AS1411‐A/hemin complex (GH) is grafted on the surface and pores of a core‐shell upconverted metal‐organic framework (UMOF) to generate a UMGH nanoplatform. Compared with UMOF, UMGH exhibits enhanced colloidal stability, increased tumor cell targeting and improved O 2 production (8.5‐fold) in situ. When irradiated by near‐infrared (NIR) light, the UMGH antitumor properties are bolstered by photodynamic therapy (PDT), thanks to its ability to convert O 2 into singlet oxygen ( 1 O 2 ). Combined with the antiproliferative activity of AS1411‐A, this novel approach lays the foundation for a new type of G4‐based nanomedicine.