# Evaluation of the toxicity and efficacy of a multi-target polymer-drug nano-polyplex in SH-SY5Y cells and Drosophila model of tauopathy

## TL;DR

This study tests a new drug delivery system in cells and fruit flies to see if it can safely reduce tau-related damage in Alzheimer's disease.

## Contribution

The novel polymer-drug nano-polyplex N5NM15 shows enhanced cell viability and reduced tau levels in neurodegenerative disease models.

## Key findings

- N5NM15 significantly improved SH-SY5Y cell viability under stress and reduced total tau levels.
- N5NM15 and PAA were toxic at higher concentrations in Drosophila models but showed mild protective effects at lower doses.
- Treatment did not improve eye-related metrics in tauopathy models.

## Abstract

Hyperphosphorylated tau contributes to synaptic damage and neuronal dysfunction in neurodegenerative diseases such as Alzheimer’s disease (AD), making it a key therapeutic target. This study evaluated the toxicity and therapeutic potential of a novel polymer-drug nano-polyplex, N5NM15, and polyacrylic acid (PAA) in Drosophila tauopathy models and undifferentiated human SH-SY5Y cells. Cellular uptake was demonstrated by N5NM15, and SH-SY5Y cell viability was significantly enhanced (45%, p ≤ 0.0001) under okadaic acid-induced stress, and total tau levels were reduced (1.43-fold, p ≤ 0.01). In comparison, PAA had a modest effect on decreasing tau phosphorylation (1.3-fold) at the pSer202/pThr205 site. Toxicity studies in Drosophila revealed that N5NM15 (3.5:1 and 44:12.5 µg/mL) and PAA (44 µg/mL) were toxic to adult flies expressing the eye-specific driver (GMR-GAL4) but were well-tolerated in flies overexpressing the pan-neuronal driver ELAV-GAL4. Furthermore, treatment with N5NM15 and PAA did not improve the ommatidial arrangement, eye bristle count, or eye length in tauopathy models. Climbing and survival assays indicated a potential mild protective effect at a lower concentration (3.5:1 µg/mL) at the early stage of the disease, but at a higher dose (44:12.5 µg/mL) was significantly toxic, in both wild-type (p ≤ 0.0001) and tauopathy models (p < 0.05). These findings highlight the need for N5NM15 and PAA dose optimisation and reformulation with non-toxic buffers to enhance therapeutic potential while minimising adverse effects in normal and Drosophila tauopathy models for AD treatment.

The online version contains supplementary material available at 10.1038/s41598-025-22924-0.