# Smart Drug-Delivery Approaches for Enhanced Management of Comorbid Conditions in Alzheimer’s Disease

## TL;DR

This paper reviews smart drug-delivery systems for Alzheimer’s disease, focusing on how they can better manage the condition and its comorbidities.

## Contribution

The paper highlights recent advances in nanotechnology-based drug delivery systems tailored for Alzheimer’s disease and comorbidities.

## Key findings

- Smart drug-delivery systems can enhance brain targeting and reduce systemic toxicity.
- Nanocarriers can modulate amyloid aggregation and neuroinflammation in Alzheimer’s.
- Controlled release platforms are critical for translational success and regulatory readiness.

## Abstract

Alzheimer’s disease (AD) remains a major unmet medical challenge due to its complex pathology, high interpatient heterogeneity and frequent association with systemic comorbidities. Conventional pharmacotherapy is limited by poor blood–brain barrier permeability, off-target effects and reduced efficacy in polymedicated elderly populations. Smart drug-delivery systems (DDS), particularly nanotechnology-based platforms, have emerged as promising strategies to enhance brain targeting, optimize controlled drug release and mitigate systemic toxicity. This review examines recent advances in intelligent DDS for AD, with a focus on nanocarriers designed to modulate amyloid aggregation, neuroinflammation, oxidative stress and cholinergic dysfunction. Special attention is given to the impact of the most common comorbid conditions on DDS pharmacokinetics, safety and clinical performance. Furthermore, the challenges associated with clinical translation, such as long-term safety, immunogenicity, manufacturing scalability and regulatory harmonization, are critically discussed. In this context, versatile controlled release platforms that integrate rational design, predictive modeling and Quality by Design-driven manufacturing are highlighted as key enablers of translational success. By bridging intelligent formulation design with scalable production and regulatory readiness, advanced controlled release systems offer a pathway toward precision and patient-centered therapies. Such platforms hold significant potential to accelerate the safe integration of smart DDS into Alzheimer’s disease management and broader neurotherapeutic applications.