A MOF-in-MOF nanoplatform for photothermal/chemodynamic therapy that enhances antitumor immunity through targeted suppression of the COX-2/PGE2 axis

To address the therapeutic limitations and metabolic toxicity associated with conventional nanocarriers, a nanostructure using an "MOF-in-MOF" strategy was engineered. The comprises an olsalazine (Olsa)-based copper metal-organic framework (Olsa-MOF) that integrates intrinsic anti-inflammatory properties and enhanced chemodynamic performance. This Olsa-MOF template is integrally enveloped by a tumor microenvironment-responsive TK-based Cu-MOF layer, which demonstrates exceptional photothermal properties. Subsequent surface functionalization with dopamine-grafted hyaluronic acid (DOPA-HA) endows active targeting ability, yielding the final nanocomposite termed Olsa@TK-Cu@HA. Olsa@TK-Cu@HA not only overcomes the limitations of conventional nanocarriers but also offers a novel strategy to enhance the therapeutic efficacy of photothermal therapy (PTT) and chemodynamic therapy (CDT) through targeted modulation of the COX-2/PGE2 inflammatory axis. The Olsa@TK-Cu@HA demonstrates a superior photothermal conversion efficiency (26.8%) and robust reactive oxygen species (ROS) generation, along with pH-responsive release of Olsa. In vitro evaluation demonstrated that Olsa@TK-Cu@HA exerts tumor-selective cytotoxicity, showing 3.5-fold higher potency against cancer cell. Moreover, Olsa@TK-Cu@HA effectively induces immunogenic cell death (ICD), as evidenced by increased extracellular ATP efflux (5.06-fold elevation) and CRT exposure. Concurrently, it downregulates the COX‑2/PGE2 axis to relieve immunosuppression in the tumor microenvironment and suppresses PD‑L1 expression. This coordinated action amplifies ICD‑mediated antitumor immunity, leading to a tumor regression rate of 84.0% in vivo. By integrating precision targeting, stimulus-responsive drug release, and immunometabolic reprogramming, this work moves beyond conventional treatment paradigms and establishes an innovative platform for next‑generation cancer therapy.