Science Advances : Significant progress! Xue Xue/Shi Bingyang/Zheng Meng developed a new delivery method to deliver siRNA to the brain to treat Alzheimer's disease.

The accumulation of toxic aggregate amyloid β is a key disease-related event in Alzheimer's disease (AD), which is caused by amyloid prelocation protein (APP) lysis through BACE1 (β-bit APP lysase 1) and γ secretion enzymes.
small interfering RNA (siRNA) shows great hope for AD therapy through the specific silence of BACE1.
, however, the lack of an effective siRNA brain delivery method limits this strategy.
October 9, 2020, Xue Xue of Nan kai University, Shi Bingyang and Zheng Meng of Henan University published a joint newsletter on Science Advances online entitled "Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer'. A research paper by s disease therapy, which developed a sugar-based "triple interaction" stable polymerization of siRNA nanoprotectives (Gal-NP s siRNA) to target BACE1 in the APP/PS1 genetically modified AD mouse model.
Gal-NP-siRNA has excellent blood stability and can effectively penetrate the blood-brain barrier (BBB) through blood sugar-controlled glucose transport protein 1 (Glut1) mediated transport, ensuring that siRNA reduces the expression of BACE1 and modifys the relative pathways.
note that gal-NP-siBACE1 dosing restores cognitive ability in AD mice without significant side effects.
this strategy supports the usefulness of RNA interference therapy in neurodegenerative diseases.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease characterized by a gradual decline in cognitive ability.
2019, AD affects more than 50 million people worldwide and is expected to reach 152 million by 2050.
, the global annual cost of AD is now $1 trillion, and is expected to double by 2030.
Currently, clinical treatment with acetylcholinesterase inhibitors or N-methyl-D-winterine-intransigent antagonists is an option for palliative care and can only moderately improve the cognition and behavior of people with Alzheimer's disease without slowing the progression of the disease.
, therefore, therapies for AD pathological mechanisms must be developed.
the exact pathological mechanism that led to AD.
, however, plaques consisting of aggregated amyloid β peptides (A beta), neurogenic fiber entanglements and nerve inflammation containing high phosphate tau proteins are pathological features of AD.
, the accumulation of A-beta abnormalities caused by BACE1 (β-bitAPP lysis enzyme 1) and γ-secretase lysate amyloid preload protein (APP) is considered a key disease-causing event of AD.
, strategies to reduce BACE1 activity and thus A-beta levels have been considered potential therapies for AD.
has been treated with BACE1 inhibitors into Phase 3 clinical trials.
, however, some BACE1 small molecule inhibitors have been shelved by pharmaceutical companies due to off-target toxicity and other safety reasons.
despite these recent failures, BACE1 is considered one of AD's most promising therapeutic targets.
Compared to small molecule-based methods, small interfering RNA (siRNA) provides promising therapies for the treatment of brain diseases by directly blocking pathogenic gene expression with high target specificity, low effective dose and relatively simple drug development processes.
siRNA in the virus vector of silent BACE1 has also been shown to improve AD neuropathology.
, however, it is still challenging to deliver siRNA to the brain as a whole, reflecting the existence of biological barriers.
recent studies have shown that nano-transport methods have great potential to overcome these challenges.
that delivering BACE1 siRNA (siBACE1) to the mouse brain by systemic injection may partially reduce AD neuropathology.
, however, treatment is not ideal due to the low brain build-up and poor stability of siRNA.
In this work, an effective, virus-free, penetrating blood-brain barrier (BBB) siBACE1 nanometer delivery method was reported, and the study evaluated it in a well-developed AD mouse model with the potential for clinical transformation.
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