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Schematic illustration of the B-LM-DMX-αCD25 nanoplatform design and its three synchronized therapeutic mechanisms: selective Treg depletion, photothermal-induced immunogenic cell death, and STING pathway activation for systemic antitumor immunity.
Image Credit: © Eijiro Miyako
Scientific Frontline: Extended "At a Glance" Summary: Blood-Camouflaged Liquid Metal Nanoparticles
The Core Concept: A multifunctional nanoplatform using liquid metal nanoparticles coated in whole-blood components to deliver a three-pronged treatment against drug-resistant triple-negative breast cancer (TNBC).
Key Distinction/Mechanism: By using whole-blood components for camouflage, the nanoparticles evade immune clearance, allowing them to accumulate in tumors at five times the efficiency of conventional nanoparticles. Once there, they deploy three synchronized mechanisms: selective depletion of regulatory T cells (Tregs), heat-induced destruction of cancer cells via near-infrared laser activation, and the targeted release of an innate immune system activator.
Major Frameworks/Components:
- B-LM-DMX-αCD25 Nanoplatform: The core delivery system, utilizing gallium-based liquid metal.
- Photothermal Therapy: Gallium-based liquid metal nanoparticles boast a heat conversion efficiency exceeding 54%, allowing a near-infrared laser to heat tumors to 58°C in five minutes, triggering immunogenic cell death.
- Treg Depletion: Anti-CD25 antibodies on the nanoparticle surface target and eliminate immunosuppressive regulatory T cells.
- STING Pathway Activation: Laser activation triggers the release of the STING agonist DMX, which stimulates innate immunity by promoting dendritic cell maturation and driving tumor-specific cytotoxic T cell responses.
Branch of Science: Oncology, Nanotechnology, Immunology, and Materials Science.
Future Application: Researchers plan to adapt this strategy for other solid tumors where immune suppression is a barrier, such as pancreatic and ovarian cancers. Development is also underway for near-infrared-II (NIR-II) laser-compatible formulations to treat deeper tumors, moving toward eventual clinical trials.
Why It Matters: TNBC is highly aggressive and lacks targetable receptors, leaving patients with limited treatment options. This nanoplatform transforms the tumor's immunosuppressive, "cold" environment into one responsive to the body's immune system, resulting in complete tumor regression and significantly extended survival in preclinical models.
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| In vivo antitumor efficacy of B-LM-DMX-αCD25 in mouse models of metastatic triple-negative breast cancer. Image Credit: © Eijiro Miyako |
Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant subtypes of breast cancer, accounting for 15–20% of all cases. Unlike other breast cancers, TNBC lacks targetable receptors, leaving patients largely dependent on chemotherapy and with limited treatment options. Even immunotherapy—an approach that has transformed cancer treatment—benefits fewer than 20% of TNBC patients, largely because tumors contain large numbers of regulatory T cells (Tregs) that suppress the immune system and prevent it from effectively attacking cancer cells.
A research team led by Professor Eijiro Miyako at the Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, has developed a multifunctional nanoplatform called B-LM-DMX-αCD25 that simultaneously addresses three key barriers to effective TNBC immunotherapy. The platform uses gallium-based liquid metal nanoparticles, a photothermal material with a conversion efficiency exceeding 54%, coated with whole-blood components. This camouflage makes the particles appear as "self" to the body, allowing them to evade immune clearance and accumulate in tumors at five times the efficiency of conventional nanoparticles.
Once at the tumor site, the platform deploys three synchronized therapeutic mechanisms. First, anti-CD25 antibodies on the nanoparticle surface selectively eliminate intratumoral Tregs, releasing the "immunological brake" that suppresses anticancer immunity. Second, near-infrared laser irradiation heats the tumor to 58°C within five minutes, destroying cancer cells and triggering immunogenic cell death. This process releases tumor antigens and danger signals that alert the immune system. Third, the STING agonist DMX, released on demand by laser activation, activates innate immunity by promoting dendritic cell maturation and stimulating the production of interferon-β, which drives tumor-specific cytotoxic T-cell responses.
In preclinical studies using orthotopic mouse models of drug-resistant TNBC, the platform achieved 100% complete tumor regression, suppressed pulmonary metastases by more than 90%, and extended median survival beyond 70 days. Comprehensive molecular analysis confirmed robust immune activation, including a more than 13-fold increase in CD3-positive T cells and an 11-fold increase in dendritic cells within treated tumors.
The researchers' strategy addresses the immunosuppressive environment that makes TNBC difficult to treat by combining tumor destruction with targeted removal of Tregs and activation of innate immunity. By coordinating these three mechanisms, the platform converts an immunologically "cold" tumor environment into one that is more responsive to the immune system.
The whole-blood camouflage strategy also provides a straightforward approach to biomimetic nanoparticle engineering. By using components of blood to help nanoparticles evade immune clearance, the researchers aim to improve their accumulation at tumor sites while retaining their therapeutic functions. The approach could potentially be adapted to other solid tumors in which immune suppression limits the effectiveness of immunotherapy.
The researchers plan to expand the platform to other solid tumor types, particularly pancreatic and ovarian cancers, where immune suppression by Tregs is also a significant challenge. They are also developing NIR-II laser-compatible formulations to extend photothermal therapy to deeper tumors. In parallel, they are preparing GLP-compliant, repeat-dose toxicology studies as part of a preclinical development package aimed at eventual clinical translation.
"We are combining three different approaches in a single nanoparticle to overcome the mechanisms that allow these tumors to evade the immune system," said Professor Eijiro Miyako. "Our next step is to determine whether this strategy can be applied safely and effectively to other types of solid tumors and eventually translated toward clinical use."
Published in journal: Advanced Science
Authors: Nina Sang, and Eijiro Miyako
Source/Credit: Tohoku University
Edited by: Scientific Frontline
Reference Number: ongy082126_01