Artesunate-loaded bovine serum albumin nanoplatform with metal–polyphenol network coating for ferroptosis-driven breast cancer therapy

ROS-responsive chitosan/hyaluronan polyelectrolyte nanogels for targeted chemo-ferroptosis therapy against breast cancer.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising strategy for combination with chemotherapy in cancer treatment. However, the rational design of delivery systems capable of simultaneously inducing ferroptosis, enhancing chemotherapy efficacy, and reducing systemic toxicity remains a substantial challenge. Herein, we developed a reactive oxygen species (ROS)-responsive, ionically crosslinked chitosan/hyaluronan polyelectrolyte nanogel for targeted chemo-ferroptosis combination therapy. In this system, hyaluronic acid (HA) was first esterified with 1,2-bis (2-hydroxyethylthio) ethylene (BE) and subsequently conjugated with methotrexate (MTX) through a ROS-cleavable linkage, yielding an anionic HA-BE-MTX polymeric prodrug. Protonated chitosan (CS) served as the cationic polymeric component, while sodium tripolyphosphate (TPP) further stabilized the nanogel network through ionic crosslinking. Sorafenib (SOR), a ferroptosis inducer, was physically encapsulated during the ionotropic gelation process. The resulting R-NGMS nanogels were designed to maintain colloidal stability under physiological conditions and to undergo ROS-triggered network loosening and drug release in the tumor microenvironment, where oxidative stress is elevated. This dual-delivery system enabled ROS-responsive MTX release and SOR-mediated ferroptosis induction, thereby promoting ROS accumulation, glutathione depletion, GPX4 suppression, lipid peroxidation, and apoptosis in breast cancer cells. In vivo studies demonstrated that R-NGMS efficiently accumulated in 4T1 tumors through prolonged circulation and HA-CD44-mediated tumor targeting, achieving a tumor growth inhibition rate of 75.85% with reduced systemic toxicity compared with free drug treatment. These findings demonstrate that ionically crosslinked CS/HA-based polyelectrolyte nanogels provide an effective and selective platform for ROS-responsive chemo-ferroptosis combination therapy.

Hyaluronic acid-decorated MOF nanoplatform loaded with berbamine elicits immunogenic ferroptosis through a sonodynamic/chemodynamic/chemotherapy synergy in triple-negative breast cancer.

Chemoresistance, inadequate tumor targeting, and severe systemic toxicity remain key barriers to effective breast cancer treatment. Ferroptosis-inducing strategies have emerged as a promising therapeutic avenue, yet their efficacy is frequently compromised by the intrinsic antioxidant defense system and insufficient immune activation within the tumor microenvironment (TME). Herein, a hyaluronic acid (HA)-functionalized, berbamine (BBM)-loaded iron-based metal-organic framework (MOF) nanoplatform (HA-FeTCPP@BBM, HAFTB) was engineered. This nanosystem executes a "three-in-one" synergistic strategy that coordinates FeTCPP-mediated sonodynamic therapy (SDT), iron-dependent chemodynamic therapy (CDT), and BBM-mediated chemotherapy and ferroptosis sensitization, while HA functionalization facilitates tumor-oriented delivery to enhance the induction of ferroptosis-associated immunogenic cell death in triple-negative breast cancer (TNBC). Upon ultrasound (US) exposure, the HAFTB scaffold functions simultaneously as a sonosensitizer and an iron source. Ultrasound activation initiates sonodynamic reactions and enhances Fenton-like catalytic activity, substantially boosting reactive oxygen species (ROS) generation. Moreover, the localized release of BBM contributes to glutathione peroxidase 4 (GPX4) suppression and weakens the cellular antioxidant defense system, thereby sensitizing tumor cells to ferroptotic stress. This tripartite oxidative stress results in extensive lipid peroxidation and robust ferroptotic cell death. Abundant damage-associated molecular patterns (DAMPs) are concurrently released, supporting the occurrence of ferroptosis-associated immunogenic responses and subsequent immune activation. In an orthotopic TNBC mouse model, HAFTB integrated with SDT achieves pronounced tumor suppression with low systemic toxicity, while transcriptomic profiling supports the involvement of ferroptosis- and oxidative stress-related pathways. Overall, the principal advance of this cascade nanoplatform lies in the coordinated integration of FeTCPP-mediated SDT, iron-dependent CDT, and BBM-associated ferroptosis sensitization within an HA-assisted MOF delivery system, providing a promising therapeutic strategy for TNBC.

Cascade-responsive biomimetic nanoparticles remodel tumor metabolism and potentiate ferroptosis for synergistic therapy of aggressive breast cancer.

In vitro and in vivo evaluations confirm that R-A/G@Z effectively suppresses aggressive breast tumors while maintaining a good safety profile, offering a promising strategy for intelligent metabolic-chemodynamic cancer nanomedicine.

Enzyme-enhanced albumin-stabilized nanopolymers for cascade catalysis-driven ferroptosis-immunotherapy.

Ferroptosis, an iron-dependent form of programmed cell death, holds significant promise for cancer therapy due to its unique redox-driven mechanism and immunogenic potential. However, its therapeutic efficacy is often compromised by inadequate catalytic kinetics and an unfavorable tumor microenvironment. Here, we develop a multifunctional nanocatalyst (BCuP@G) based on albumin-stabilized polypyrrole doped with multivalent Cu ions and conjugated with glucose oxidase (GOx) to enable enzyme-enhanced cascade catalysis for ferroptosis-immunotherapy. The embedded Cu+/Cu2+ redox centers catalyze glutathione depletion and ·OH generation, while GOx continuously supplies H2O2 through glucose oxidation. Upon NIR-II laser irradiation, the photothermal effect further accelerates both enzymatic and catalytic kinetics, triggering excessive redox imbalance, lipid peroxidation, and synergistic ferroptosis-apoptosis. Moreover, BCuP@G demonstrates effective tumor accumulation and potent antitumor efficacy, particularly in combination with anti-PD-1 therapy, which promotes tumor-associated macrophage repolarization and T cell infiltration. This study presents a robust cascade-catalytic nanoplatform that integrates redox modulation and immune activation for advanced ferroptosis-enhanced cancer immunotherapy.

A cascade-amplified Fe3O4-based nanoplatform for miRNA-21 sensing and combined apoptosis/ferroptosis induction

A Ferrous-Supply-Regenerating Lipid Nanoparticle Integrating RNAi Induces Ferroptosis for Cancer Therapy.

Targeting iron-dependent ferroptosis with siRNA has emerged as a promising strategy for cancer treatment. The concept of ferrous-supply regeneration, inspired by electro-Fenton technology, has also gained interest as a non-apoptotic approach to induce ferroptosis. However, integrating both strategies into a single lipid nanoparticle (LNP) remains challenging. To address this, we developed ALSF, a novel LNP in which DSPC is replaced with arachidonic acid (AA) to enable co-delivery of Glutathione Peroxidase 4-siRNA (GPX4-siRNA) and Fe3 +. ALSF facilitates acid- and H2O2-dependent iron recycling, continuously regenerating Fe2 + to drive ROS production, while GPX4-siRNA silences GPX4 to induce lipid peroxidation (LPO) and ferroptosis. Elevated H2O2 levels in cancer cells promote selective iron recycling, lysosomal disruption, and siRNA escape, enabling effective gene knockdown at lower doses. In vivo, ALSF suppressed tumor growth in a C918 xenograft model with favorable biosafety. This study is the first to integrate a ferrous-supply-regeneration system with siRNA into a single LNP platform, offering a selective ferroptosis-inducing strategy for ocular cancers and other ferroptosis-sensitive malignancies.