Singapore's National University of Singapore (NUS) is at the forefront of biomedical innovation with a transformative breakthrough in precision cancer therapy. Researchers led by Assistant Professor Andy Tay from the Department of Biomedical Engineering have developed smart gold nanoparticles equipped with unique DNA barcodes. These nanoparticles enable high-throughput screening to identify designs that precisely target the mitochondria—the powerhouses of cancer cells—disrupting their energy production and triggering cell death. This advancement, published in the journal Advanced Materials on February 17, 2026, promises to revolutionize nanomedicine by accelerating the design of effective drug delivery systems.

The technology addresses a critical hurdle in cancer treatment: delivering therapies exactly where needed inside tumors while minimizing damage to healthy tissues. Traditional methods often fail due to biological barriers like poor circulation, limited tumor penetration, and endosomal entrapment. NUS's approach uses multiplexing to test dozens of nanoparticle variants simultaneously in living models, generating over 1,000 data points with 30 times fewer animals than conventional testing. This efficiency not only speeds up discovery but also aligns with ethical research standards upheld by Singapore's universities.

Why Mitochondria Matter in Cancer Therapy

Mitochondria, often called the 'power plants' of cells, produce adenosine triphosphate (ATP), the energy currency essential for cellular functions. In cancer cells, these organelles are hyperactive, fueling rapid proliferation, metastasis, and resistance to therapies. Disrupting mitochondrial function can halt energy supply, induce apoptosis (programmed cell death), and sensitize tumors to other treatments like chemotherapy or immunotherapy.

Full name: Mitochondria (singular: mitochondrion). They have their own DNA and are inherited maternally. Cancer mitochondria exhibit altered metabolism, known as the Warburg effect, where cells prefer glycolysis even in oxygen-rich environments. Targeting them offers a selective vulnerability, as normal cells rely less on these pathways. NUS researchers exploited this by engineering nanoparticles to deliver small interfering RNA (siRNA) that silences key mitochondrial genes, such as ATP synthase 6 (ATP6), combined with photothermal therapy—mild heating via near-infrared light to amplify damage.

Overcoming Biological Barriers: The Nanoparticle Journey

Gold nanoparticles (AuNPs) are ideal for therapy due to their biocompatibility, tunable size (1-100 nm), shapes (spheres, cubes, rods), and optical properties for imaging and heating. However, their path to mitochondria involves four hurdles:

• Systemic circulation: Avoiding clearance by the reticuloendothelial system (RES) via stealth coatings like polyethylene glycol (PEG).
• Tumor accumulation: Exploiting the enhanced permeability and retention (EPR) effect in leaky tumor vasculature.
• Cellular uptake: Via endocytosis pathways, influenced by particle shape—cubes favor clathrin-mediated entry.
• Subcellular delivery: Escaping endosomes and reaching mitochondria, aided by ligands like triphenylphosphonium (TPP) for positive charge attraction.

NUS's platform reveals that tumor accumulation is a prerequisite for mitochondrial success, challenging assumptions that size or shape alone dictates outcomes.

The DNA Barcode Revolution in Screening

The core innovation is DNA barcoding: short, unique oligonucleotide sequences (20-30 bases) attached to each nanoparticle variant. These barcodes are stable, amplifiable via PCR, and quantifiable by next-generation sequencing (NGS). Here's the step-by-step process:

1. Library design: Synthesize 30 AuNP variants (e.g., 40/80 nm spheres/cubes/rods with PEG, TPP, folic acid (FA), hyaluronic acid (HA), or cRGD ligands).
2. Pooling and injection: Mix equal amounts, inject intravenously into tumor-bearing mice (subcutaneous, orthotopic models).
3. Extraction and sequencing: Dissect tumors/organs, isolate mitochondria, sequence barcodes to map distribution at organ, cellular (tumor cells vs. macrophages), and subcellular levels.
4. Data analysis: Normalize reads to identify top performers; correlate properties with efficacy.

This multiplexed in vivo screening outperforms in vitro tests, where cubic particles underperformed but excelled in tumors due to protein corona effects prolonging circulation.

Standout Nanoparticles: Cubic and Spherical Stars

From the library, two shone: 80 nm folic acid-modified cubic (CL-FA) and spherical (PL-FA) AuNPs. CL-FA excelled in cellular uptake via clathrin endocytosis and curvature-sensing proteins, reaching high mitochondrial levels. PL-FA benefited from a de-opsonin-rich corona for longer blood half-life. Both accumulated 5-10 times more in tumors than controls, correlating with mitochondrial delivery (r=0.85).

Therapeutic Triumph: 99% Tumor Regression

In preclinical breast cancer models, CL-FA loaded with ATP6-siRNA and activated by mild photothermal therapy (PTT, 45°C) achieved 99% tumor regression after one dose—near-complete elimination. Controls showed <20% reduction. No recurrence observed over 60 days, vs. regrowth in monotherapies. Stats: Tumor volume reduced from 200 mm³ to <5 mm³; survival >90% vs. 40%.

Mechanism: siRNA silences ATP6, starving mitochondria; PTT amplifies stress. Synergy: RNA interference + heat disrupts metabolism synergistically.

Reprogramming the Tumor Microenvironment

Beyond direct killing, CL-FA shifted tumor-associated macrophages (TAMs) from pro-tumor M2 to anti-tumor M1 phenotype (CD86+ increase 3-fold, Arg1- decrease). This immune modulation enhances long-term efficacy, reducing metastasis risk. TAMs, comprising 50% of tumor mass, normally suppress immunity; reprogramming turns them into allies.

NUS's Role in Singapore's Biomedical Ecosystem

NUS, ranked Asia's top university, drives Singapore's biotech hub ambitions under the Research, Innovation and Enterprise (RIE2025) plan, allocating S$25B for R&D. The College of Design and Engineering's Biomedical Engineering department, with iHealthtech, fosters interdisciplinary work. This breakthrough aligns with S$50M precision oncology funding (SYMPHONY 2.0), collaborating with A*STAR and NTU. Singapore's 6% GDP R&D spend (highest Asia) positions NUS researchers like Prof Tay for global impact, attracting talent via scholarships and postdoc programs.

• Singapore's cancer incidence: 55,000 cases/year, rising 3%/year.
• NUS contributions: 20% national biomed output.
• Impact: Trains 1,000+ PhDs/year in nanotech-related fields.

Behind the Innovation: Asst Prof Andy Tay and Team

Asst Prof Andy Tay, expert in biomaterial-immune interfaces, leads with PhD from Stanford. Quote: “Nanoparticle design is complex; our platform uncovers interactions beyond trial-and-error.” Co-authors: Xingyue Huang (lead), Xuehao Tian et al., blending engineering, biology. Funded by NUS startups, NMRC.

Future Outlook: Scaling to Clinics

Next: Larger libraries (100+ designs), AI data analysis, other organelles (nucleus, ER). Clinical translation via NUS Enterprise spin-offs. Singapore's regulatory sandbox accelerates nanomedicines. Globally, reduces animal use 30-fold, costs; potential for RNA vaccines, CRISPR delivery.

Challenges: Scale-up synthesis, human EPR variability, long-term safety. Optimism high: 99% efficacy paves way for phase I trials by 2028.

Singapore Universities Leading Nanomedicine Charge

NUS collaborates with NTU (nanofilm labs), Duke-NUS (clinical trials). NTU's SMART center advances similar platforms. A*STAR's IMCB complements with manufacturing. Case: Prior NUS magnetoelectric nanoparticles for deep tumors. Singapore's ecosystem: 200+ biotech firms, Biopolis hub.

Student impact: Programs like NUS BME MSc produce experts; internships at iHealthtech.

Photo by Markus Spiske on Unsplash