A tumor microenvironment-responsive and mannose-mediated MnO2-based nano-delivery system for synergistic targeted chemotherapy in triple-negative breast cancer.
Jul 2026· Nanomedicine: Nanotechnology, Biology and Medicine· pp.
103000
· 0 citations· 26 references
Medicine
TL;DR
By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO2@Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.
Abstract
Triple-negative breast cancer (TNBC) remains a formidable challenge due to its aggressive progression and the absence of established therapeutic targets. This study engineered a multifunctional, tumor microenvironment (TME)-responsive nanoplatform MnO2@Man/DOX, which was designed for synergistic targeted chemotherapy and TME modulation. The platform comprises a manganese dioxide (MnO2) core for redox regulation and a mannose (Man) shell for active targeting and metabolic sensitization, stabilized with bovine serum albumin and sodium dodecyl sulfate. MnO2@Man/DOX nanoparticles are nearly spherical (289 nm) and exhibit dual-responsiveness by efficiently depleting intracellular glutathione and catalyzing endogenous hydrogen peroxide into cytotoxic hydroxyl radicals via Fenton-like reactions. In vitro, the nanoplatform demonstrated a remarkable 8-fold reduction in IC50 (0.52 μg/mL) compared with free doxorubicin (4.2 μg/mL) in 4 T1 cells. Transcriptomic analysis suggested that MnO2@Man/DOX is associated with TNF signaling and apoptosis-related pathways, including extrinsic, intrinsic, and endoplasmic reticulum stress-mediated programs. In vivo evaluations in 4 T1 tumor-bearing mice confirmed preferential tumor accumulation and superior growth inhibition with a high biosafety profile, including a hemolysis rate below 5% and minimal systemic toxicity. By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO2@Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.
Conventional chemotherapeutic agents are frequently limited by off-target toxicity and suboptimal therapeutic outcomes. Nanomedicines utilizing cell membrane camouflage provide a promising strategy for precise drug delivery and multimodal combination therapy. Herein, we designed a tumor-microenvironment-responsive cell-membrane-coated nanocomposite (designated as ZnO2@MO-D@Mn-CeO2@CM), which consists of a zinc peroxide (ZnO2) core encapsulated within a drug-loaded mesoporous organosilica (MO-D, where D is doxorubicin for the 4T1 breast cancer model and daunorubicin for the C1498 leukemia model) layer, with the mesopores gated by manganese-doped cerium oxide (Mn-CeO2) nanoparticles, and coated with a homologous cell membrane (CM). This nanocomposite enables the release of therapeutic components under acidic conditions and in the presence of elevated glutathione (GSH). It facilitates a combination therapy by integrating chemotherapy, enhanced chemodynamic therapy (CDT), ferroptosis induction, and immunomodulation. Our results demonstrate that this nanocomposite effectively suppresses the progression in 4T1 solid tumor and C1498 leukemia models, demonstrating its potential as a robust combinatorial strategy.
Tong Wang, Yingying Wang, Jianxiang Xu et al.· ACS Applied Materials and In...· 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
Although strategic combination of cuproptosis and chemotherapy is emerging as a promising strategy against triple-negative breast cancer (TNBC), current drug delivery systems remain considerable challenges in achieving co-delivery of different formulas, such as complex nanocarrier design, limited drug loading capacity, and insufficient tumor targeting. Herein, cancer cell membrane-camouflaged, self-assembled nanoparticles (DCM@CCM) were fabricated for precision combination therapy against TNBC. In the strategy, the carrier-free self-assembled nanoparticles were one-pot fabricated by co-assembling copper ions (Cu2+), doxorubicin (DOX), and methotrexate (MTX) via hydrogen bonds, π-π stacking and metal-ligand coordination effect, followed by in situ camouflaging with cancer cell membranes. Benefiting from the homologous targeting effect, the developed DCM@CCM could specifically target tumor cells, promoting their cellular uptake. Following internalization into tumor cells, the DCM@CCM disassembled in response to a weakly acidic tumor microenvironment, releasing Cu2+, DOX, and MTX. Importantly, the Cu2+ was reduced to Cu+ by depleting intracellular glutathione, which not only activated cuproptosis but also catalyzed the endogenous hydrogen peroxide into highly toxic hydroxyl radicals via a Fenton-like reaction, resulting in mitochondrial dysfunction. Simultaneously, both DOX and MTX disrupted DNA synthesis to trigger cell apoptosis. Both in vitro and in vivo experiments indicated that DCM@CCM exhibited potent cytotoxicity against TNBC cells and effectively suppressed tumor growth in heterotopic tumor models with minimal side effects. Overall, our study not only provides a promising strategy for precision combination therapy against TNBC but also expands insight for developing nanoscale self-assembly-enabled nanomedicine.
Qian Liu, Xinyi Tao, Yawen Luo et al.· ACS Applied Bio Materials· 0 citations
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype lacking effective targeted therapies. Its tumor microenvironment (TME) exhibits distinct features, including acidity, redox imbalance, elevated reactive oxygen species (ROS), and hypoxia, which provide exploitable triggers for targeted drug delivery. Stimuli-responsive polymeric nanocarriers have emerged as promising platforms that enable spatiotemporally controlled and site-specific therapeutic release in response to these endogenous cues, as well as exogenous stimuli such as temperature and light. These systems improve drug accumulation, penetration, and therapeutic efficacy while reducing systemic toxicity. Unlike previous reviews that broadly discuss nanocarriers in cancer therapy, this review focuses on the structure–function relationships of TME-responsive polymeric systems in TNBC and their translational limitations. We summarize recent advances in pH-, redox-, ROS-, hypoxia-, photo- and temperature-responsive polymers, highlighting their design strategies and therapeutic applications. Key challenges, including stimulus heterogeneity, limited in vivo validation, and clinical translation barriers, are also discussed. This review provides a concise framework for the rational design of programmable, multi-responsive polymeric nanomedicines for TNBC therapy.
Adnan Murad Bhayo, Ying Li, Alaa R. Aboushanab et al.· Pharmaceutics· 0 citations
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, poses a substantial global health challenge with high mortality and poor therapeutic outcomes, especially in advanced stages. Current therapeutic approaches for HCC, including surgical resection, targeted therapy, immunotherapy, and radiotherapy, are often limited by drug resistance, systemic toxicity, and the complex tumor microenvironment (TME). Herein, we establish the first wool keratin-guided Mn3O4 nanozymes (MnWK) with self-cascade catalytic capability that systematically transforms the TME into a pro-oxidative microenvironment, achieving high therapeutic efficacy through synergistic hypoxia alleviation and ROS-mediated apoptosis. The introduction of WK not only enhances the biocompatibility and colloidal stability of Mn3O4 nanoparticles, but also improves their catalytic performance to enable efficient cascade reactions under physiological conditions. Within the mildly acidic and H2O2-rich TME, MnWK exhibits dual catalase (CAT) and oxidase (OXD)-mimicking activities, driving a well-defined two-step catalytic cascade. Specifically, it first decomposes endogenous H2O2 into O2 to effectively alleviate tumor hypoxia, then converts the in situ generated O2 into cytotoxic superoxide anions. This cascade amplifies oxidative stress and induces selective cancer cell apoptosis via the p38/JNK MAPK signaling pathway. Overall, this work establishes a promising TME-adaptive self-cascade nanotherapeutic system for advancing HCC management.
Hongji Wu, C. Fan, Qikuan He et al.· Small· 0 citations
BIMLM is developed as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication.
Boye Zhang, Yuli Chen, Pengyan Qiao et al.· Journal of Advanced Research· 0 citations