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In silico design and physicochemical characterisation of a dual-action intranasal nanoparticle formulation for Alzheimer’s disease
Rao R, Kar V, Webb B.. Research Square, 2026-09-28
Topic: Disease mechanisms in lab and animal studies
Approved Alzheimer’s disease therapies fail to address the two drivers of cognitive decline: loss of BDNF-TrkB signalling and accumulation of hyperphosphorylated tau protein. We designed and evaluated an intranasal poly(lactic-co-glycolic acid) (PLGA) nanoparticle co-loading two small molecules − 7,8-Dihydroxyflavone, a TrkB agonist, and EF24, a curcumin analog that binds to tau. The design was evaluated across molecular docking, molecular dynamics, ADMET prediction, pharmacokinetic simulation, and nanoparticle synthesis and characterisation. Among four compounds tested, 7,8-Dihydroxyflavone showed the strongest predicted TrkB binding (ΔG = -9.079 kcal mol⁻¹), exceeding donepezil and memantine, while EF24 showed the strongest predicted tau binding (-5.068 kcal mol⁻¹) and comparable GSK-3β affinity to other compounds. Over 20 ns molecular dynamics simulations, both candidates remained stably bound to their targets (ligand RMSD ≤ 3.1 Å), whereas both approved drugs dissociated. Both compounds were predicted to be blood-brain-barrier permeant and drug-like, with predicted median lethal doses exceeding those of the approved comparators. Intranasal delivery increased predicted brain exposure over oral administration across all pharmacokinetic metrics. Nanoparticles synthesised across three batches were consistent in size, dispersity and surface charge, falling within published specifications for intranasal delivery (152 nm; polydispersity 0.21; zeta potential − 26 mV). These findings identify this approach as a mechanistically grounded candidate warranting further in-vitro and in-vivo validation.
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APA 7th
Rao, R., Kar, V., & Webb, B. (2026). In silico design and physicochemical characterisation of a dual-action intranasal nanoparticle formulation for Alzheimer’s disease. Research Square. https://doi.org/10.21203/rs.3.rs-10822803/v1
Vancouver
Rao R, Kar V, Webb B. In silico design and physicochemical characterisation of a dual-action intranasal nanoparticle formulation for Alzheimer’s disease. Research Square. 2026. doi:10.21203/rs.3.rs-10822803/v1.
BibTeX
@article{rao2026-29a49622,
author = {Rao, R. and Kar, V. and Webb, B.},
title = {{In silico design and physicochemical characterisation of a dual-action intranasal nanoparticle formulation for Alzheimer’s disease}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10822803/v1},
url = {https://doi.org/10.21203/rs.3.rs-10822803/v1}
}
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Key findings
- These findings identify this approach as a mechanistically grounded candidate warranting further in-vitro and in-vivo validation.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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