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Breaking Boundaries in the Brain with Small Apoptotic Bodies

Scientists have discovered small apoptotic bodies that can be loaded with drugs and cross the blood-brain barrier, bringing new promise to combat cerebrovascular diseases.

Cell death and cancer may sound frightening at first glance, but scientists have come up with a novel way to manipulate these two phenomena to remedy devastating brain diseases.

Brain disease is a blanket term encapsulating a wide range of illnesses, from common ones like Alzheimer’s and Parkinson’s to less prevalent ones like amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease.

Diseases afflicting the brain are among the most complex and difficult to cure, primarily due to the obstructive “barrier”, known as the blood-brain barrier (BBB). Under normal circumstances, this BBB serves as a defensive layer that protects our brain from circulating toxins or pathogens. However, this protective barrier also restricts the movement of drugs administered to combat cerebrovascular diseases, hence calling the need for more efficient brain drug delivery strategies.

Recently, scientists have turned to an unexpected player, apoptotic bodies, in their search for solutions. Apoptotic bodies (ABs) refer to tiny membrane-bound vesicles, which bud off dying cells during apoptosis. Akin to garbage bags that neatly organise trash for disposal, they contain the DNA, organelles, proteins, and other parts of the obsolete cell that need to be eliminated by phagocytic cells. This removal occurs in a non-inflammatory fashion to ensure that the parts of the cell do not spill out onto surrounding cells and cause damage.

The existence of ABs has long been established, but their potential as drug delivery agents has remained unrecognised, and for good reason. ABs are known to have uneven size distribution and complex composition, making them unsuitable drug-carrying candidates. However, several new studies have suggested otherwise, claiming that these ABs may have more to offer beyond recycling functions.

Researchers from Nanjing University and the University of Macau have brought to light a new potential use for nano-scaled apoptotic bodies (ABs) – as delivery agents of brain-targeting drugs. The team has successfully extracted small apoptotic bodies (sABs), which confound initial theories about ABs’ poor eligibility as a drug carrier, bringing new hope for treating brain diseases like Parkinson’s Disease among many others.

Scientists compared sABs with micron-sized apoptotic bodies and found that sABs are considerably more uniform in size, contained much fewer DNA fragments and more RNAs. These sABs were reportedly stable in serum and can be circulated in vivo for longer periods without the worry of being engulfed by phagocytes. They also exhibited high drug loading efficiency and offer better control and productivity. Additionally, since sABs originally bud off from cell membranes, the molecules on the cell membrane are preserved on the vesicles. This feature is especially useful to incorporate targeting ligands.

To further demonstrate the viability of sABs, the team first extracted the antisense oligonucleotide (ASO) of tumour necrosis factor-alpha (TNF-α), which is a signalling protein from skin cancer cells that have metastasized or spread to the brain. TNF-α is widely used as a topical therapy to curb tumours and cancers due to its ability to trigger necrosis or apoptosis of cells, in other words, cell death.

The TNF-α ASO was then loaded into sABs and injected into mice test subjects. Based on their findings, the sABs demonstrated a remarkable capacity to penetrate the BBB and effectively deliver the anti-inflammatory ASO to the microglia, alleviating the development of Parkinson’s disease.

With exceptional delivery and targeting capabilities, researchers foresee that sABs derived from cancer cells can transform current methods of diagnosis, prognosis, and treatment of brain diseases, overcoming the bottleneck of exosome-based therapeutics and becoming a new class of drug carriers. The versatility of sABs is expected to open new doors for more effective and better-targeted drug delivery systems for previously untreatable neurodegenerative diseases. [APBN]

Source: Wang et al. (2021). Delivering Antisense Oligonucleotides across the Blood-Brain Barrier by Tumor Cell-Derived Small Apoptotic Bodies. Advanced Science, 2004929.