# From Polyphenols to Prodrugs: Bridging the Blood–Brain Barrier with Nanomedicine and Neurotherapeutics

## TL;DR

This review explores how to overcome the blood-brain barrier to deliver plant-based neurotherapeutics using nanomedicine and prodrug strategies.

## Contribution

The paper proposes a co-design framework for neurotherapeutics that integrates chemistry, delivery methods, and measurement to improve translation.

## Key findings

- Phytochemicals face BBB challenges due to tight-junction selectivity and efflux transporters.
- Nanocarriers, intranasal delivery, and prodrugs can enhance brain exposure of plant-derived compounds.
- Co-design of chemistry, carrier, and delivery route improves therapeutic outcomes and trial success.

## Abstract

Central nervous system disorders drive disability, yet many neuroactive candidates fail because the brain is a hard compartment to dose. Plant-derived molecules spanning polyphenols, alkaloids, terpenoids, and cannabinoids are attractive because their pleiotropic actions can engage oxidative stress, neuroinflammation, and circuit dysfunction. In practice, the blood–brain barrier (BBB) restricts most native phytochemicals through tight-junction selectivity, rapid metabolism, low solubility, and transporter-mediated efflux. Key gaps include poor standardization of exposure metrics, limited human-relevant BBB models, and few head-to-head studies that compare delivery platforms on the same payload and outcome. This review tackles the mismatch between mechanistic promise and reliable brain exposure that stalls translation. The objectives are to link phytochemical liabilities to enabling strategies in nanomedicine, alternative routes, and transporter-targeted prodrugs, and to propose decision-grade endpoints for translation. We synthesize evidence on BBB transport logic, nanocarrier families, targeting ligands, intranasal delivery, focused ultrasound-mediated opening, and prodrug approaches that hijack influx transporters, while foregrounding safety and chemistry, manufacturing, and controls (CMC) constraints. Here we highlight that effective neurotherapeutics emerge when chemistry, carrier, route, and measurement are co-designed rather than optimized in isolation. This framework can guide platform selection, de-risk first in-human studies, and sharpen trial endpoints. More broadly, it offers a transferable playbook for barrier-limited drug development across neurology, psychiatry, and oncology.