What question did this study set out to answer?

This research aims to develop a novel nanostructure that improves antitumor therapy while minimizing metabolic toxicity.

May 21, 2026Open Access

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

Key Points

This research aims to develop a novel nanostructure that improves antitumor therapy while minimizing metabolic toxicity.
Engineered an olsalazine-based copper MOF layered with a tumor-responsive TK-based Cu-MOF for targeted drug delivery.
Functionalized the surface with dopamine-grafted hyaluronic acid to enhance targeting and enable release in the tumor microenvironment.
Conducted in vitro evaluations to measure cytotoxicity and immunogenic cell death effects alongside in vivo tumor regression assessments.
Olsa@TK-Cu@HA achieved a tumor regression rate of 84.0% in vivo, demonstrating significant therapeutic efficacy.
Induced immunogenic cell death with a 5.06-fold increase in extracellular ATP and enhanced CRT exposure.
Showed 3.5-fold higher potency against cancer cells with superior photothermal conversion efficiency of 26.8% and increased ROS generation.

Abstract

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.

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