Aug 2026· Colloids and Surfaces B: Biointerfaces· Vol 268 Pt 2, pp.
116071
· 0 citations· 59 references
Medicine
TL;DR
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.
Abstract
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.
Hepatocellular carcinoma (HCC) remains highly lethal due to a complex tumor microenvironment (TME) that limits therapeutic efficacy. Herein, a dual-targeted nanotherapeutic platform (SC@GRT-COF-366) based on a covalent organic framework (COF-366) is reported for synergistic HCC treatment. This multifunctional system integrates chemotherapy, photodynamic therapy, autophagy regulation, and TME remodeling to synergistically inhibit tumor metastasis. Gal-D5HT-modified nanoparticles achieve enhanced HCC targeting via myeloperoxidase (MPO)-responsive aggregation in the inflammatory microenvironment and ASGPR-mediated uptake. Upon light irradiation, COF-366 generates singlet oxygen to induce tumor cell apoptosis and simultaneously enhances MPO expression and neutrophil infiltration, further amplifying MPO-triggered nanoparticle aggregation and establishing a self-amplifying retention-therapy cascade. Meanwhile, co-loaded sorafenib and chloroquine enable combined chemotherapy and autophagy inhibition, effectively overcoming drug resistance. In vivo results demonstrate significantly enhanced and prolonged tumor accumulation compared with single-targeted systems, resulting in a tumor growth inhibition rate of 93.5 ± 1.02% in subcutaneous models and effective suppression of lung metastasis in orthotopic HCC models. Notably, treatment markedly reduces neutrophil extracellular traps (NETs) formation, indicating favorable remodeling of the tumor immune microenvironment. Collectively, this multifunctional COF-based nanoplatform integrates dual-targeted delivery, amplified tumor retention, and synergistic multimodal therapy, offering a promising strategy for advanced HCC treatment.
Le Wang, Xiang Wang, Hengrui Li et al.· Small· 0 citations
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.
Tumor hypoxia diminishes antitumor immunity by stabilizing HIF-1α, promoting M2-like macrophage polarization, and impairing cytotoxic T-cell activity. To reverse these effects, we developed hemoglobin-loaded biomimetic nanoparticles (Hb-BNPs) using a modified nanoprecipitation strategy. The nanoparticles encapsulate hemoglobin within a polycaprolactone matrix and are cloaked with RBC/A549 membranes to provide immune camouflage and sustained oxygen release. This study evaluates their ability to reoxygenate the tumor microenvironment and restores immune and therapeutic responses in non-small-cell lung carcinoma (NSCLC).
Hb-BNPs were synthesized via modified nanoprecipitation and membrane cloaking. Physicochemical features were assessed by DLS, TEM. Hypoxia was induced in A549 cells, followed by Hb-BNP treatment. qRT-PCR, paclitaxel IC50 assays, 3D spheroids, LunX CAR-T cytotoxicity, and KANK1-transfection studies evaluated immunologic and therapeutic responses (all n = 3, ANOVA/t).
Under hypoxia, HIF1A, VEGF, BNIP3, ENO1, HK1, PGK1 were upregulated by 5—8-fold (p < 0.01). After Hb-BNP reoxygenation, these genes were downregulated by 4—6-fold (p < 0.001), and dissolved oxygen increased 5.3-fold (p < 0.001). Oxygen recovery improved the immune function as LunX CAR-T cytotoxicity increased 2.3-fold (p < 0.01), and KANK1-driven transgene expression increased 2.7-fold (p < 0.05). Co-treatment with paclitaxel reduced IC50 from 25,612 ng/mL to 781 ng/mL (p < 0.0001) and enhanced 3D spheroid core cell death 2.4-fold (p < 0.01). Hb-BNPs did not elevate IL-6, TNF-α, or IL-8 in THP-1 macrophages, confirming immune tolerance.
Hb-BNPs reoxygenate hypoxic tumors, suppress HIF-1α signaling, and restore cytotoxic immune function without inducing inflammation. By normalizing oxygen balance, these biomimetic nanoparticles enhance CAR-T activity, gene transfection, and chemotherapy response, offering a scalable, immune-tolerant platform to overcome hypoxia-driven resistance in solid tumors.
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Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
H.A. Gandhi, Jaydeep Bhattacharya· Journal of Immunology· 0 citations
This review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition, and the key bottlenecks hindering clinical translation.
Yuxuan Ma, Jie Gong, Zixuan Wu et al.· International Journal of Nan...· 0 citations
Photodynamic therapy (PDT) holds promise for combination antitumor therapies by triggering immunogenic cell death (ICD). ICD is defined as the process by which tumor cells, upon death induced by external stimuli, convert from a non‑immunogenic to an immunogenic state, thereby mediating an anti‑tumor immune response in the host. But the poor aqueous solubility and inadequate tumor targeting of photosensitizers hinder their clinical translation. This study focuses on a novel BODIPY photosensitizer (M5) and aims to improve its antitumor efficacy via efficient tumor-targeted delivery and controllable release. Herein, we successfully synthesized iRGD-functionalized DSPE-PEG2000-iRGD and pH-sensitive HA-g-DEAP polymers, and further fabricated multifunctional M5/NMN/DEAP/iRGD-Lip liposomes via the thin-film dispersion method, which possess pH responsiveness and enhanced tumor-targeting ability. β-Nicotinamide Mononucleotide (NMN), a NAD + precursor, exerts a potent stimulatory effect on T-cell activation; 3-(Diethylamino)propylamine (DEAP) and hyaluronic acid (HA) can form pH-responsive HA-g-DEAP; the iRGD peptide (CRGDK/RGPDC), upon hydrolysis at its C‑terminus, exposes a motif that binds to neuropilin‑1 (NRP1), thereby conferring tumor‑targeting and tissue‑penetrating properties, endowing the liposomes with tumor-targeting and tissue-penetrating capabilities. M5 exhibits a high molar absorption coefficient of 5.33 × 104 M⁻¹ cm⁻¹ and a singlet oxygen quantum yield of 0.3854. In vitro cellular assays showed IC50 values of 104.1 nM and 72.68 nM in breast cancer MDA-MB-231 and 4T1 cells, respectively. Treatment with M5/NMN/DEAP/iRGD-Lip induced apoptosis rates of 56.84% and 55.6% in MDA-MB-231 and 4T1 cells, respectively. T-cell co-culture assays showed that M5/NMN/DEAP/iRGD-Lip increased the proportions of CD4+ and CD8+ T cells while reducing the proportion of regulatory T cells (Tregs) among CD4+ T cells. Collectively, the multifunctional M5/NMN/DEAP/iRGD-Lip liposomes integrate targeted delivery, pH-controlled release, and synergistic PDT-immunotherapy, effectively addressing key limitations of conventional photosensitizers. This work provides a promising nanoplatform for the development of novel combination therapies against breast cancer, laying a foundation for future preclinical and clinical translations.
Junwei Zhuang, Chen Guo, Xingming Ye et al.· Colloids and Surfaces B: Bio...· 0 citations
Summary Traditional chemotherapy for breast cancer faces limitations, including poor drug bioavailability, multidrug resistance, and severe systemic side effects. Therefore, a carrier-free nanodrug composed of Mastoparan M (Mast-M, derived from Wasp toxin), FDA-approved near infrared fluorescence dye (indocyanine green, ICG), and biosafe ion Fe3+ was developed to achieve photothermal (PTT) and synergistic chemodynamic therapy (CDT)-assisted oxidation therapy. Once accumulated within tumor sites by enhanced permeability and retention (EPR) effects, the Mast-M/Fe3+/ICG rapidly dissociates in response to elevated glutathione (GSH), releasing Fe2+, ICG, and Mast-M. Mast-M efficiently triggers reactive oxygen species (ROS) generation to induce mitochondrial membrane potential disruption. Fe2+-mediated CDT further amplifies oxidative stress, accompanied by GSH consumption and lipid peroxide (LPO) accumulation. Under laser irradiation, ICG generates hyperthermia to enhance oxidative stress. In vitro and in vivo studies demonstrated enhanced antitumor efficacy with reduced systemic toxicity. Together, these findings highlight the potential of carrier-free nanodrugs for oxidative stress-based breast cancer therapy.
Hairong Zhao, Chen Yang, Shuangyan Bao et al.· iScience· 0 citations
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