MRI-enabled ferroptosis self-amplifying nanoplatform synergizes with photothermal therapy to enhance chemotherapeutic efficacy against pancreatic cancer
This study presents a synergistic nanotherapeutic strategy that integrates chemotherapy, photothermal therapy, and ferroptosis-related mechanisms to overcome chemoresistance in pancreatic cancer.
Abstract
Pancreatic cancer responds poorly to conventional chemotherapy, largely because of the pronounced resistance of tumor cells to chemotherapy-induced apoptosis. Ferroptosis, a non-apoptotic form of programmed cell death, has emerged as a promising strategy to overcome this resistance. However, its therapeutic efficacy is often limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) in the tumor microenvironment (TME). Herein, we developed a nanoplatform, HM-MnO2@DOX/CaO2@PDA/HA (HMDCPH), using hollow mesoporous manganese dioxide (HM-MnO2) as a carrier to co-deliver doxorubicin (DOX) and calcium peroxide (CaO2). The crosslinked PDA/HA shell enhanced both the tumor-targeting capability and biocompatibility of the nanoplatform. In the TME, HM-MnO2 depleted GSH and promoted reactive oxygen species (ROS) generation, whereas CaO2 decomposition generated H2O2 and released Ca2+, inducing mitochondrial calcium overload and further aggravating oxidative stress. These synergistic effects enhanced lipid peroxidation (LPO) and exacerbated ferroptosis-related oxidative damage. Moreover, the near-infrared (NIR)-triggered photothermal effect further strengthened the antitumor efficacy of HMDCPH. In addition, nanoplatform degradation released Mn2+, enabling T1-weighted magnetic resonance imaging (MRI). Collectively, this study presents a synergistic nanotherapeutic strategy that integrates chemotherapy, photothermal therapy, and ferroptosis-related mechanisms to overcome chemoresistance in pancreatic cancer.
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
Cerium molybdate-doped polyaniline nanoparticles are developed to enable a synergistic combination of photothermal therapy (PTT) and CDT, thereby triggering immunogenic cell death (ICD) and enhancing antitumor immunity and presenting a robust nanoplatform integrating chemodynamic and photothermal therapies for potent cancer immunotherapy.
Yulin Kuang, Cheng Lu, Bolan Yu et al.· Bioactive Materials· 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
PANoptosis, a newly characterized form of inflammatory programmed cell death that integrates multiple cell death modalities, offers distinct advantages in both potent tumor cell killing and activation of antitumor immunity. However, strategies that can effectively induce PANoptosis in tumor cells remain scarce. Herein, we constructed a tumor microenvironment-responsive nanoplatform (HA-MnO2-FTY720@CaO2, HMFC) comprising a CaO2 core and a MnO2 shell, loaded with fingolimod (FTY720) and surface-functionalized with hyaluronic acid (HA) for CD44-mediated targeting. Under the mildly acidic and glutathione (GSH)-rich conditions of the tumor microenvironment (TME), the MnO2 shell degrades, liberating FTY720 and exposing the CaO2 core. The CaO2 subsequently decomposes to release Ca2+ and H2O2. FTY720 inhibits Transient Receptor Potential Melastatin 7 (TRPM7) channels, disrupting Ca2+/Mg2+ homeostasis and thereby provoking severe calcium overload. Simultaneously, MnO2 depletes GSH and, together with CaO2-derived H2O2, promotes a Fenton-like reaction that generates abundant reactive oxygen species (ROS), thereby disrupting intracellular redox homeostasis. In addition, Mn2+ released from MnO2 degradation activates the cGAS–STING pathway, further contributing to DC maturation and antitumor immunity. This orchestrated immune response markedly suppresses tumor growth and when combined with anti-PD-L1 therapy, induces a pronounced abscopal effect. Together, our results indicate that calcium overload, FTY720-mediated TRPM7 inhibition, and MnO2-induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.
Aiyang Tong, Yang Zhou, Yang Ding et al.· Materials Today Bio· 0 citations
By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO2@Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.
Guanghui Mei, Hanwen Wang, Xinhua Lin et al.· Nanomedicine: Nanotechnology...· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) remains difficult to treat because of inefficient intracellular drug delivery and robust redox defense. Here, we developed a glutathione (GSH)-responsive biomimetic nanoplatform, termed CMnMG, for magnetic resonance (MR) imaging and gemcitabine (GEM) chemotherapy. CMnMG was prepared by loading GEM into manganese-doped mesoporous silica nanoparticles and coating them with SW1990 pancreatic-cancer-cell membranes. The membrane coating enhanced homologous tumor cell uptake and reduced macrophage internalization. After cellular uptake, GSH triggered the degradation of the manganese-containing framework, leading to GSH consumption and the release of GEM and Mn2+. This process increased intracellular drug availability and weakened antioxidant defenses. Released Mn2+ also promoted reactive oxygen species generation in the presence of endogenous H2O2, thereby enhancing the GEM-induced cytotoxicity. Meanwhile, paramagnetic Mn2+ increased the T1-weighted MR contrast. Thus, CMnMG therefore offers a GSH-responsive strategy for improving GEM chemotherapy and T1-weighted MR imaging of pancreatic cancer.
Shuai He, Jian Chen, Pan Yang et al.· ACS Applied Nano Materials· 0 citations