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.
INTRODUCTION
Strategic harnessing and modulation of the tumor microenvironment (TME) can overcome its inherent therapeutic barriers and enhance treatment efficacy. TME hallmarks, including hypoxia, excessive glutathione (GSH), and insufficient H2O2, severely limit reactive oxygen species (ROS)-based therapies.
METHODS
To address this issue, leveraging the high lactate level in TME, we developed BIMLM (BSA-IR780-MnO2@LOX@Membrane) as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation. BIMLM was fabricated by first preparing MnO2-coated IR-780 nanoparticles, then immobilizing LOX, and finally cloaking them with tumor cell membranes. After BIMLM accumulates selectively within tumor tissue, intratumoral excess lactate triggers the sequential therapeutic cascades. Specifically, LOX-catalyzed lactate oxidation generates H2O2 to induce metabolic starvation by disrupting energy supply. This H2O2 is then decomposed by MnO2 to produce O2, which simultaneously facilitates cyclic lactate oxidation and enhances photodynamic therapy (PDT). The resulting Mn2+ further triggers a Fenton-like reaction, converting the self-supplied H2O2 into •OH and thereby amplifying chemodynamic therapy (CDT). Concurrently, GSH depletion increases cellular susceptibility to ROS, further potentiating both PDT and CDT. Notably, coordinated GSH downregulation and ROS upregulation synergistically trigger ferroptosis, which combines with apoptosis to achieve potent tumor suppression.
RESULTS
Taken together, the nanoplatform reconfigures the TME through lactate depletion, H2O2 elevation, hypoxia alleviation, and GSH scavenging. This series of changes creates a self-amplifying cycle that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication. This strategy establishes a promising paradigm for high-efficiency tumor therapy.
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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.
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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.
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