Red Blood Cell Hitchhiking Delivers Oxygen and Paclitaxel to Crush Drug-Resistant Breast Cancer Metastases

Triple-negative breast cancer is the most unforgiving form of the disease: it proliferates aggressively, spreads early, and resists nearly every chemotherapy thrown at it. When it metastasizes to the lungs, it becomes the primary driver of death in patients with this subtype. Now, a team of researchers in China has engineered a biomimetic drug delivery system that hijacks the body’s own red blood cells to ferry a two-punch payload—oxygen-carrying hemoglobin and the chemotherapy drug paclitaxel—directly into lung metastases, where it dismantles the molecular machinery of drug resistance and triggers a form of cell death that chemotherapy alone cannot achieve. The work, published in Materials Today Bio, describes a system called RBC-LEHP that produced a reduction in tumor burden of roughly three orders of magnitude in a mouse model compared with conventional paclitaxel liposomes.

The central obstacle the researchers set out to overcome is a vicious cycle linking low oxygen to drug resistance. Solid tumors, especially aggressive ones like triple-negative breast cancer, are chronically starved of oxygen because their hastily built blood vessels are irregular and dysfunctional. Oxygen can only diffuse about 100 to 200 micrometers from a functioning vessel, leaving tumor cores severely hypoxic. In this oxygen-poor environment, a transcription factor called hypoxia-inducible factor-1 alpha, or HIF-1α, becomes stabilized and switches on genes for ATP-binding cassette transporters—most notably P-glycoprotein, the efflux pump encoded by ABCB1. P-glycoprotein literally pumps chemotherapeutics like paclitaxel back out of the cell, rendering them useless. Blood transfusions and hyperbaric oxygen therapy can ease systemic hypoxia, but neither reliably relieves hypoxia inside the tumor itself.

Previous attempts to solve this problem have used hemoglobin-based oxygen carriers, since hemoglobin is the body’s natural oxygen transporter and can also catalyze the generation of reactive oxygen species. But free hemoglobin degrades rapidly, is dose-dependently toxic, and provokes systemic inflammation. Liposome-encapsulated hemoglobin improves stability, yet conventional formulations lack spatial precision, often pooling in the liver and spleen. The new study, led by Xunyi You and colleagues with senior author Ye Cao, took a different route: rather than relying on passive accumulation, the team attached their drug-loaded liposomes loosely to the surfaces of intact red blood cells—a strategy known as RBC hitchhiking.

The concept is elegantly physical. The liposomes bind to red blood cells through weak, reversible interactions such as van der Waals forces and electrostatic attraction, without being internalized. When the cell-liposome complexes are injected intravenously, they travel through the bloodstream until they squeeze through narrow capillaries. The shear forces in these tight passages mechanically scrape the nanoparticles off the red cell surfaces and transfer them to the capillary endothelium, dramatically increasing accumulation in the first capillary-rich organ downstream of the injection site. For drugs injected into a tail vein, that organ is the lung—precisely where triple-negative breast cancer metastasizes. The team’s earlier work had already shown that combining liposomes with RBC hitchhiking extends blood half-life and boosts pulmonary accumulation.

Building on that foundation, the researchers formulated liposomes from the phospholipid DPPC, the pH-sensitive lipid DOPE, and cholesterol, encapsulating both paclitaxel and purified hemoglobin in a single nanoparticle. The resulting LEHP particles measured between 100 and 200 nanometers in diameter with a polydispersity index below 0.2, indicating a highly uniform population, and transmission electron microscopy confirmed smooth, spherical structures. Paclitaxel encapsulation efficiency was 83.32 percent for hemoglobin-free liposomes and 58.27 percent for the hemoglobin-loaded version, the reduction likely reflecting the protein occupying space in the aqueous core. Critically, the hemoglobin inside LEHP showed a P50 of about 10.20 mmHg—substantially lower than the roughly 26.5 mmHg of normal adult hemoglobin—meaning a left-shifted oxygen dissociation curve and enhanced oxygen loading in the pulmonary circulation, with favorable release under the low-oxygen conditions of the tumor.

The hitchhiking step itself proved remarkably gentle on the carrier cells. After optimizing the ratio of liposomes to red blood cells, confocal microscopy showed liposomes uniformly coating the erythrocyte membranes while preserving their native biconcave disc shape. The engineered cells maintained their CD47 expression—the “don’t eat me” signal that prevents clearance by the immune system—showed no significant increase in phosphatidylserine exposure, retained normal osmotic fragility profiles, and kept their deformability index unchanged, preserving the mechanical flexibility needed to squeeze through splenic sinuses and lung capillaries.

Inside tumor cells, the payload executes a coordinated attack on two fronts. First, delivered hemoglobin alleviates hypoxia, which destabilizes HIF-1α and removes the transcriptional activation of ABCB1, sharply downregulating P-glycoprotein and restoring the cell’s vulnerability to paclitaxel. Second, the iron released from hemoglobin fuels the Fenton reaction, converting hydrogen peroxide into highly reactive hydroxyl radicals. The team documented the three hallmarks of ferroptosis—an iron-dependent form of cell death driven by lipid peroxidation: elevated labile ferrous iron, surging lipid peroxides, and a collapse of mitochondrial membrane potential. Molecular analysis showed LEHP suppressing the antioxidant guardian GPX4 and its regulator Nrf2 along with the cystine transporter SLC7A11, while upregulating the transferrin receptor, driving NCOA4-mediated ferritinophagy to liberate stored iron, and boosting ACSL4 to supply polyunsaturated fatty acid substrates for membrane oxidation. When cells were pretreated with ferrostatin-1, a specific ferroptosis inhibitor, LEHP-induced cell death was profoundly reversed—confirming ferroptosis as the dominant killing mechanism, with a minor complementary contribution from apoptosis at high drug concentrations.

The DOPE lipid added a self-amplifying delivery trick. In the acidic lysosome, DOPE destabilizes membranes and releases hemoglobin; the liberated ferrous iron then generates radicals that attack the polyunsaturated fatty acids concentrated in the lysosomal membrane itself. That peroxidation increases membrane permeability, accelerating the escape of both hemoglobin and paclitaxel into the cytosol—a ROS-dependent positive feedback loop that the team observed as early as two hours after treatment. The researchers describe the net effect as “re-oxygenation injury”: chronically hypoxic cells, adapted to survive without oxygen, are suddenly overwhelmed by an oxygen influx that their antioxidant defenses cannot absorb, triggering a catastrophic oxidative collapse.

In vivo, the advantages compounded. In mice bearing 4T1 breast cancer lung metastases, RBC-hitchhiked liposomes produced a 2.7-fold increase in pulmonary fluorescence intensity and a 4.6-fold improvement in the lung-to-liver ratio compared with liposomes alone, with lung signals persisting up to 48 hours. In the therapeutic experiment, paclitaxel monotherapy failed to arrest tumor progression, and each partial strategy—hemoglobin without hitchhiking, or hitchhiking without hemoglobin—fell short on its own. Only the fully integrated RBC-LEHP platform achieved sustained regression: at the day 13 endpoint, pulmonary bioluminescence in the RBC-LEHP group was (7.70 ± 2.86) × 10⁴, roughly three orders of magnitude below the LEP group’s (2.19 ± 0.37) × 10⁷. Histology showed intact bronchial architecture and no edema or fibrosis in treated lungs, with no systemic toxicity in the heart, liver, spleen, or kidneys, and reduced Ki67 proliferation, CD31-marked microvessel density, and MMP2 and MMP9 metastasis markers.

Perhaps most strikingly, the treatment remodeled the tumor immune microenvironment, markedly increasing infiltration of CD4-positive and CD8-positive T cells and shifting the lung tumors from an immunologically cold state toward an inflamed, hot one. High-throughput proteomics of lung tissue confirmed the mechanism at the systems level: NCOA4 upregulation and GPX4 downregulation enforcing ferroptotic commitment, HIF-1α and P-gp suppression restoring chemosensitivity, and suppression of the epigenetic driver EZH2 and the pro-survival factor CEBPB dismantling the tumor’s transcriptional survival programs. The authors caution that some hepatic accumulation was observed at 24 hours, though without histological signs of liver damage, and that systemic immune responses in peripheral lymphoid organs remain to be profiled. Still, the study establishes a compelling template—targeted delivery, hypoxia alleviation, ferroptosis plus chemotherapy, tumor suppression—that could extend beyond breast cancer to any malignancy whose resistance is rooted in the oxygen-starved depths of the tumor.

Subject of Research: A biomimetic erythrocyte-hitchhiking liposome system delivering hemoglobin and paclitaxel to overcome hypoxia-driven chemoresistance in triple-negative breast cancer lung metastasis via ferroptosis

Article Title: Oxygen-augmented erythrocyte-liposome hybrids to overcome paclitaxel resistance in triple-negative breast cancer metastasis via enhanced ferroptosis

Article References: You, X., Zhu, K., Li, W., Wang, H., Zhong, R., Li, S., Liu, J., Wong, Y. S., Venkatraman, S. S., & Cao, Y. (2026). Oxygen-augmented erythrocyte-liposome hybrids to overcome paclitaxel resistance in triple-negative breast cancer metastasis via enhanced ferroptosis. Materials Today Bio, 41, Article 103705. https://doi.org/10.1016/j.mtbio.2026.103705

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103705

Keywords: triple-negative breast cancer, ferroptosis, red blood cell hitchhiking, liposomes, tumor hypoxia, HIF-1alpha, P-glycoprotein, paclitaxel, drug resistance, lung metastasis, hemoglobin, nanomedicine