Hyaluronic acid-decorated MOF nanoplatform loaded with berbamine elicits immunogenic ferroptosis through a sonodynamic/chemodynamic/chemotherapy synergy in triple-negative breast cancer.
Aug 2026· Biomaterials Advances· Vol 189, pp.
215124
· 0 citations· 35 references
Medicine
TL;DR
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.
Abstract
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.
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.
A. Gao, Fengyu Wang, Xiaonan Cui et al.· International Journal of Bio...· 0 citations
Triple-negative breast cancer (TNBC) represents the most aggressive form of breast cancer and is associated with the worst prognosis. Ferroptosis holds great promise as an emerging therapeutic strategy; however, TNBC cells demonstrate reduced sensitivity to ferroptosis as a result of elevated mitochondrial membrane potential (MMP), inadequate production of reactive oxygen species (ROS), and the presence of activated antioxidant defencses, making it difficult for lipid peroxidation to accumulate to a lethal threshold. As an emerging therapeutic strategy, sonodynamic therapy (SDT) is particularly suitable for deep-seated tumors due to the excellent tissue penetration capabilities of ultrasound (US). Nevertheless, current sonosensitizer typically experience limited sonodynamic efficacy and inadequate targeting of tumors, whereas small interfering RNA (siRNA) presents a highly promising option for gene therapy, its efficacy is heavily dependent on efficient and safe cellular delivery vectors. Therefore, we designed and synthesized a folate-modified Fe-TCPP metal-organic framework (FTFA) nanoplatform that serves both as a siATAD3A gene therapy carrier and as a sonosensitizer to generate ROS upon ultrasound (US) irradiation. ATAD3A displays high expression levels in TNBC and is linked to a negative prognosis; it's silencing reduces MMPs and increases ROS-induced apoptosis. siATAD3A was loaded onto FTFA to prepare FTFA@siATAD3A, which was delivered to TNBC cells via folate receptor-mediated targeting. Under US irradiation, the Fe3+ loaded within this platform synergistically triggers a ferroptosis cascade involving the Fenton reaction, lipid peroxidation, and GPX4 downregulation, effectively inducing ferroptosis. This method greatly reduces the proliferation of cells, as well as their migration and tumor growth when tested in living organisms, and it also shows excellent compatibility with biological tissues. In summary, FTFA@siATAD3A provides a novel strategy for the synergistic gene-ferroptosis therapy of TNBC using sonodynamic effects.
Yang Du, Jiang N. Yang, Shuai Chen et al.· ACS Biomaterials Science & E...· 0 citations
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.
Nianting Xiao, Xiao He, Daxiu Li et al.· Journal of Colloid and Inter...· 0 citations
Current clinical interventions for solid tumors are confronted with multiple prominent challenges, including intratumoral hypoxia, constitutively activated endogenous antioxidant defense systems, and inefficient tumor targeting. In this study, a multifunctional nanoliposome carrier is developed by co-encapsulation of hemoglobin (Hb), ferric citrate (FC), and chlorin e6 (Ce6), and surface-modified with the iRGD (CRGDKGPDC) peptide to facilitate active tumor targeting and enhance subsequent intratumoral penetration. Under ultrasound irradiation, the iRGD-targeted nanoliposomes can efficiently generate two distinct types of reactive oxygen species (ROS) to produce strong synergistic cytotoxicity against 4T1 breast cancer cells via separate pathways: singlet oxygen (1O₂) through the sonodynamic therapy (SDT) pathway, and hydroxyl radicals (·OH) through the chemodynamic therapy (CDT) pathway. In vivo experimental results show that tail vein injection (i.v.) of iRGD-targeted nanoliposomes combined with external ultrasound irradiation achieves can significantly enhance tumor growth inhibition, which is attributed to triggered on-demand drug release induced by ultrasound. The as-prepared iRGD-targeted nanoliposomes exhibit remarkable synergistic antitumor efficacy, inducing extensive tumor necrosis, apoptosis, and ferroptosis while causing minimal systemic side effects, demonstrating great application potential for future breast cancer therapy.
Runming Zhong, Yingzhe Wu, Yanzhen Lou et al.· Colloids and Surfaces B: Bio...· 0 citations
BACKGROUND
Our preliminary study found that Men1 is an oncogene and a potential therapeutic target in gastric cancer (GC). Chemotherapy remains a common therapeutic regimen for GC, but is frequently limited by multidrug resistance and poor intratumoral coordination of combination drugs. Targeting Menin may enhance chemotherapy sensitivity, but efficient co-delivery of Menin inhibitors and chemotherapeutics is hindered by the profound spatiotemporal pharmacokinetic decoupling of the drugs in vivo.
METHODS
We first evaluated the synergistic antitumor effect and Menin/p53-associated mechanism of BMF-219 combined with 5-fluorouracil (5-FU) in gastric cancer models. We then engineered a hierarchically assembled, cascade-responsive hyaluronic acid (HA)-decorated liposome/mesoporous silica nanoplatform (HLM@BF) for coordinated co-delivery of BMF-219 and 5-FU. The system features a glutathione (GSH)-degradable disulfide-bridged mesoporous silica core, cloaked with a pH-sensitive lipid bilayer and decorated with HA for targeting. The synergistic efficacy and biological mechanism were evaluated through bioinformatic analysis, RNA sequencing (RNA-seq), in vitro assays, and in vivo experiments.
RESULTS
BMF-219 sensitized GC cells to 5-FU-induced apoptosis through modulation of Menin- and p53-associated apoptotic signaling. HLM@BF was constructed successfully, and showed colloidal stability in serum-containing medium, pH/GSH-responsive co-delivery, enhanced CD44-associated uptake, endo/lysosomal redistribution or escape, increased tumor accumulation, and suppressed xenograft growth with favorable biosafety.
CONCLUSIONS
HLM@BF integrates Menin inhibition with 5-FU chemotherapy and enhances antitumor efficacy through Menin- and p53-associated apoptotic signaling, providing a targeted nanomedicine strategy for gastric cancer.
Shanhu Wang, Dongsheng Li, Fanshuo Zeng et al.· Journal of experimental & cl...· 0 citations
Conventional nanoparticles for tumor imaging and therapy often fail due to poor clearance, prolonged circulation, and toxic off-target effects. We introduce a biomimetic phytic acid (PA)–metal–albumin nanoternary complex that repurposes the body’s natural PA–metal–protein assembly/clearance axis to enable tumor-targeted theranostics. The platform is serum-stable, bioclearable, and supports a broad spectrum of imaging and therapeutic payloads. For example, PA chelates manganese (Mn2+) for high-contrast T1-weighted magnetic resonance imaging, platinum (Pt) for chemotherapy, and radium-223 (Ra-223) for alpha radiotherapy. In the acidic environment of tumor endosomes, the complexes undergo programmed aggregation to maximize intratumoral retention, while systemic elimination follows physiological detox pathways. Released Mn2+ enhances cGAS–STING immune activation, amplifying antitumor responses. This clearance-competent, biomimetic nanoplatform unifies imaging, therapy, and immune modulation, advancing precision oncology with strong translational potential.
