Precision targeting of the CNS: recent progress in brain-directed nanodrug delivery

 Didn't your competent? doctor and hospital get directed drug delivery going a long time ago? Oh no, THEY DID NOTHING?

So you incompetently don't follow research at all?

If we had a complete database of stroke research this problem would be solved in no time. Getting thru the blood brain barrier, maybe one of these?

Overcoming the Blood–Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours

May 2020

LIPOSOMES FOR BRAIN DRUG DELIVERY  February 2020 

Exosomes as drug delivery vehicles for therapeutic proteins to the brain February 2019 

Miniaturized system delivers drugs to the brain with pinpoint accuracy February 2018 

Nanowires could be potential drug delivery tools for neurodegenerative diseases

 November 2017

Nose2Brain – Better Therapy for Multiple Sclerosis April 2017 

Novel Alzheimer's treatment uses microscopic droplets of fat to carry drugs into the brain October 2016 

New Technology Shows Promise for Delivery of Therapeutics to the Brain 

 October 2014

Nose-to-Brain Drug Delivery by Nanoparticles in the Treatment of Neurological Disorders July 2014 

Brain Targetting through Intranasal Route November 2013 

exosomes delivering drugs to brain March 2011

 And that is as far as I go back, so there are probably lots more.

 The latest here:

Precision targeting of the CNS: recent progress in brain-directed nanodrug delivery

Dinithi Senanayake, Piumika Yapa, Sanduni Dabare and Imalka Munaweera*
Department of Chemistry, Faculty of Applied Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka. E-mail: imalka@sjp.ac.lk; dinithisenanayake3@gmail.com; piumikayapa@gmail.com; dabaresanduni@gmail.com

Received 21st May 2025 , Accepted 5th July 2025

First published on 21st July 2025

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Abstract

The therapeutic drug penetration into brain tissues meets limitations through the restrictive function of the blood–brain barrier (BBB) within the central nervous system (CNS). The advancement of nanocarrier engineering techniques allows scientists to develop nanoscale delivery vehicles that successfully cross the BBB. This review analyses modern brain-delivery nanodrug delivery platforms by examining the properties and distribution of liposomes and polymeric nanoparticles, dendrimers, solid lipid nanoparticles, and exosomes. Organizations use specific physicochemical approaches designed for each platform to boost brain penetration and enhance therapeutic drug distribution for improving drug effectiveness. An analysis is presented of the various procedures to cross or bypass the BBB where receptor-mediated transcytosis joins focused ultrasound, as well as magnetic targeting and chemical modifications. The article presents therapeutic developments regarding neurological treatment of Alzheimer's disease, alongside Parkinson's disease and glioblastoma. Early laboratory success has produced promising results, yet challenges persist during the translation of these findings for clinical use because of safety issues as well as compatibility problems and difficulties with scaling up manufacturing processes. Finally, it discusses regulatory advancements and describes active market trends in nanomedicine that focus on precise delivery techniques and combination treatment methods, and brain-targeted delivery systems. The innovations combined present an optimistic future for CNS drug development because they create substantial opportunities to reshape neurological disorder treatments.

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1. Introduction

The blood–brain barrier (BBB) constitutes a select interface which operates between blood and brain tissue to manage molecular transfers and provides protection to the central nervous system (CNS).1,2 Complex cellular and molecular mechanisms drive the BBB development process until endothelial cells acquire their permeability-specific properties. Three primary functions are contained in the term “BBB”: brain protection from blood environment, transport (preferably selective), and metabolism or alteration of substances derived from blood or produced by the brain. The development of the BBB phenotype is dependent on some associated brain cells – mainly astrocytic glia – and is formed from complex tight junctions and various mechanisms of intracellular transport and enzymes responsible for controlling the flow of molecules across the cell membranes. The establishment of the BBB is developing, integrating characteristics of endothelial cells such as controllable permeability, high electrical resistance, and expression of certain transporters and metabolic pathways. The BBB operates using tight junctions alongside specific transport systems as well as metabolic pathways which act together to determine substance movement. The BBB maintains vital homeostasis of the brain tissue and helps nutritive substance uptake and functions as an essential defense against toxins and neuroactive substances.3,4 The functioning of the BBB depends on CNS microenvironment-induced regulatory procedures. BBB dysfunction produces different neuropathological problems while researchers currently study methods to manipulate the barrier for therapeutic applications. The development of CNS therapy requires fundamental knowledge about how BBB operates because it serves as a critical foundation for creating specific drug delivery methods.

Nanotechnology revolutionized drug delivery through solutions for therapeutic problems which include poor therapeutic specificity and undesirable effects. The drug protection capabilities of nanoparticles stretch from 5 to 200 nanometers while allowing precise drug delivery. The delivery method boosts treatment performance while minimizing adverse effects together with enhancing patient treatment experience. The use of nanotechnology in developing drugs can improve the effectiveness of drug delivery systems by increasing its accuracy towards the intended site. This would minimize the harmful effects of the drug to healthy cells. Furthermore, it can improve patient comfort, ease the fluctuations in drug plasma concentration, and lower the overall cost of the product due to high solubility and efficiency. The nanoparticle (NP) is of the utmost importance, since it serves as a carrier that can be conjugated with various drugs using different techniques so that medications can be delivered to the intended site. Specific ligands bound to the NP surface enhance cell targeting, while the co-polymers protect immunologically active cells. The drug-bioconjugate nanoparticle system will be able to reach the affected area, bind to the target cell membrane, and subsequently be internalized through receptor-mediated endocytosis. Afterward, the NPs can controllably supply the medication directly to the disease location. The drug carrier technology utilizes nanoparticles along with polymers and proteins and lipids to develop drug transport structures. These structures include nanoparticles, liposomes and micelles.5 A targeting ligand and programmed release system can be integrated into nanocarrier platforms during their design stage. Research conducted regarding nanotechnology reveals promising delivery results in cancer therapy and antiviral treatments as well as cell transplantation. The investment of pharmaceutical companies in this field will drive nanotechnology-based drug delivery systems towards improving outcomes for patients suffering from critical illnesses.6

Through nano-scale technology, researchers can provide successful drug delivery systems to CNS tissue through methods that bypass both the BBB and blood-cerebrospinal fluid barrier (BCSFB) restrictions.7,8 Nanoparticles of different types including polymeric nanoparticles and solid lipid nanoparticles and liposomes and micelles demonstrate the potential to cross the BBB through endocytic or transcytic pathways.9 The combination of nanotechnology methods has shown preclinical effectiveness for treating CNS ailments starting from Alzheimer's disease up to Parkinson's disease and brain tumors and stroke.7–9 Nanocarriers enhance drug body processing parameters while providing targeted brain tissue delivery systems. Optimal performance of drugs used to fight trafficking and increased specificity along with reduced neurotoxicity need additional development.7,10 Extra research is necessary to address nanomedicine toxicity and develop standardized procedures for enabling successful CNS drug delivery translations to clinical settings.

2. Challenges in CNS drug delivery

2.1 BBB permeability

The tight junctions of the blood–brain barrier along with its selective permeability function as a major obstacle for drug delivery to central nervous system disorders. Research groups have explored different methods to defeat the blood–brain barrier resistance through drug delivery vehicles combined with chemical and physical targeting methods and techniques that break down the barrier. Research indicates that nanoparticles along with colloidal carrier systems may serve as useful tools in CNS drug delivery systems.11,12 Scientists study mechanistic and technological methods to enhance brain disorder drug bioavailability.13 New in vitro models attempt to replicate BBB functions but there is a research challenge to maintain accurate BBB behavior while satisfying pharmaceutical industry requirements for high-volume testing.14

As an interface the BBB regulates substance exchange between bloodstream components and CNS materials to maintain brain environment stability. The BBB exists as a structural framework that consists of brain microvascular endothelial cells joined by tight junctions along with pericytes and astrocytic end-feet and basement membrane for a complete neurovascular unit (NVU).15 The barrier ensures constrained paracellular diffusion by having tight junctions that use claudins along with occluding and junctional adhesion molecules (JAMs) to selectively regulate molecular transport across the barrier.16 The BBB controls essential nutrient entry through carrier-mediated transport along with receptor-mediated transcytosis that also allows waste products to cross the barrier along with essential nutrients. The protective mechanisms of the BBB represent an obstacle to medicine delivery because the tight barrier function prevents penetration by large hydrophilic therapeutic agents. Knowledge of how the BBB functions and what structure it possesses becomes essential to develop effective approaches that let drugs pass through this boundary for neurological disorder care.17

2.2 Limited drug penetration and bioavailability

The ability to transfer drugs into the CNS is one of the key challenges mainly attributed to the inclusive nature of BBB. The BBB consists of tightly connected endothelial cells backed by astrocytes and pericytes creating a highly selective barrier permeable only to particular substances, usually small (<400 Da), lipophilic, and non-ionized molecules that can pass through the barrier through passive diffusion.11,18 Therefore, most drugs, particularly macromolecules and hydrophilic molecules cannot accumulate to therapeutic levels in the brain, thus greatly reducing their therapeutic application in the treatment of neurological diseases, including Alzheimer, Parkinson, and brain tumors.19 Active efflux processes serve to limit bioavailability of drugs in the CNS, on top of minimal permeability. Molecular pumps (efflux transporters) on the luminal surface of brain capillary endothelial cells (especially P-glycoprotein, or P-gp) recognize and transfer a broad assortment of xenobiotics and therapeutic agents back into the systemic circulation.20,21 This mechanism greatly decreases the concentration of many drugs in the brain even those that may succeed in getting across the BBB. Doan et al.22 provided evidence that marketed CNS drugs are likely to be both high passive permeability and low affinity to P-gp-mediated efflux, which indicated that transporter activity was critical in defining the success of CNS drugs. In addition, P-gp and additional transporters namely BCRP and MRPs act as added barriers to add to the poor penetration of most therapeutics.20

These two issues, limited penetration and active transportation out, require the inventions of new drug delivery methods. Strategies including nanoparticle-based delivery vehicles, drug chemical optimization, receptor-mediated transport and intranasal administration have demonstrated potential in evading or altering the BBB to increase CNS exposure.13 An in-depth knowledge of the structural characteristics of the BBB together with an understanding of the molecular actions of efflux transporters is inevitable in developing therapeutic agents that can easily bypass the BBB to exert their curing effects on the brain tissues.

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