DNA‑barcoded Gold Nanoparticles that Deliver Therapy Directly to Cancer Cell Mitochondria.

Cancer drugs often fail not because they are weak, but because they never reach the exact place they are supposed to act, all the way down to the tiny structures inside tumour cells. Researchers at the National University of Singapore have developed a new way to search for nanoparticles that can carry treatment directly to mitochondria, the “power stations” inside cancer cells, by testing many particle designs at the same time in living tumours. In preclinical models, one of their best designs almost completely removed tumours when used to deliver a genetic drug together with gentle heat therapy.

The team works with gold nanoparticles, very small particles thousands of times thinner than a human hair. Gold is useful in medicine because it is chemically stable, can be coated with different molecules, and heats up when exposed to near infrared light, which can be used to damage tumour tissue in a controlled way, a method called photothermal therapy. The key problem in nanomedicine is that changing the size, shape or surface of a particle changes how it behaves in the body, and until now most groups had to test one formulation at a time in animals, which is slow and gives limited information.

To break this bottleneck, the NUS group introduced DNA barcodes. Each nanoparticle design is tagged with a short stretch of DNA that acts like a unique ID. The researchers built a library of 30 different gold nanoparticle formulations that varied in shape, size and surface ligands, for example the presence of folic acid to help particles recognise certain cancer cells. They then mixed all of these in one solution and injected the pool into tumour bearing animal models.

After treatment, they collected samples from different organs, tumour tissues, cell populations and finally from mitochondria inside tumour cells. Using next generation DNA sequencing, they read out how much of each DNA barcode was present in each sample. This tells them, in one experiment, which nanoparticle designs reach the tumour, which enter cancer cells, and which make it all the way to mitochondria. This multiplexed approach produced more than one thousand in vivo data points while using roughly thirty times fewer animals than testing each formulation separately, which is important both for speed and for animal welfare.

The data revealed a simple but important rule. Nanoparticles that accumulated well in tumours were also much more likely to be found in mitochondria, while designs that stayed mostly in the bloodstream or in healthy organs rarely reached this subcellular target.

Within their library, two types of particles performed especially well. Large spherical particles coated with folic acid built a protective protein layer in the blood that allowed them to circulate longer and build up strongly in tumours. Large cubic gold nanoparticles entered cancer cells efficiently through clathrin mediated endocytosis, a common cellular uptake pathway, and these cubic particles were particularly good at reaching mitochondria once inside the cells.

The team then tested the cubic design in a therapeutic setting. They loaded these nanoparticles with small interfering RNA, a type of genetic drug that silences specific genes, here aimed at disrupting mitochondrial gene expression in tumour cells. At the same time, they used the gold core as a heater by applying near infrared light to the tumour area, producing mild photothermal therapy that stresses tumour cells without strongly burning surrounding tissue. When both effects were combined in preclinical models, the treatment led to almost complete tumour elimination after a single dose, with about ninety nine percent regression reported.

The treatment also seemed to influence the immune environment. Tumour associated macrophages, immune cells that often help tumours grow, shifted toward a more tumour fighting state after therapy, suggesting that the nanoparticles can both damage cancer cells directly and reprogram local immune cells in a favourable way. This is important because long lasting responses in cancer usually require involvement of the immune system, not only direct killing of tumour cells.

The main impact of this work is the platform itself. By combining DNA barcoding, high throughput sequencing and subcellular fractionation, the researchers can systematically map how features like size, shape and surface chemistry control nanoparticle behaviour at organ, cellular and mitochondrial levels in vivo. This moves the field away from slow trial and error and toward data driven design of “smart” nanoparticles for cancer and potentially other diseases. The group plans to expand the nanoparticle library, apply automation and artificial intelligence to analyse the growing data sets, and eventually extend targeting to other organelles inside cells.

Source.