Nanoparticle (NP)-based drug delivery systems offer promising solutions for neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, which have no cure due to the brain's structural complexity and the restrictive nature of the blood-brain barrier (BBB). Conventional therapeutics, despite strong in vitro efficacy, often fail clinically due to poor brain penetration. Recent advances in NP engineering, including optimization of size (10-100 nm), surface charge (-10 to -20 mV), and targeted ligand decoration, have improved BBB crossing and reduced premature clearance. In parallel, predictive in silico approaches, such as physiologically based pharmacokinetic (PBPK) modeling, computational fluid dynamics, and machine learning models, enable quantitative prediction of NP biodistribution, residence times, and region-specific uptake. By simulating key determinants, including blood flow dynamics, vasculature heterogeneity, permeability, and retention, these computational tools accelerate lead selection, reduce experimental burden, and inform design before in vivo testing. This review integrates recent progress in NP design with advanced computational modeling, highlighting how their convergence provides a rational framework for developing next-generation brain-targeted therapeutics. We further discuss regulatory and translational challenges, including safety, biocompatibility, and the need for humanized preclinical benchmarks. Together, these innovations offer a roadmap for advancing NP-based strategies toward clinical impact in neurodegenerative disease.

Oral nanomedicine offers a promising strategy to enhance drug bioavailability, yet engineering strategies are most effectively evaluated not as isolated features but as sequential decision nodes, because a choice at one barrier mechanically constrains the strategy space at the next. This review presents a barrier-sequenced analytical framework that evaluates nanoparticle strategies at each stage by mechanistic causality, oral-specific evidence quality, and downstream design constraint. Within each barrier category, strategies were distinguish and validated by multiple oral in vivo studies from those supported by limited oral data or remaining at the proof-of-concept stage, and identified the physiological boundary conditions (fed versus fasted states, inflammatory disease, and chronic dosing) under which each principle holds. This review further maps how a formulation choice at one barrier mechanically constrains the strategy space at the next, revealing which multi-barrier combinations are compatible and which are antagonistic. Finally, This review assesses physiologically based pharmacokinetic modeling and machine learning against their current data prerequisites, framing them as hypothesis-generating aids with explicit infrastructure gaps rather than decision-grade design engines. By extracting generalizable design principles and their limits, this framework aims to guide mechanism-informed, patient-centered oral nanotherapies.

Fusaric acid (5-butylpicolinic) is a mycotoxin produced by Fusarium species as a biological response to external environmental factors. It exhibits hepatotoxicity in humans upon consumption of contaminated agricultural products. The compound was first reported nearly 92 years ago by Yabuta et al. Interestingly, Fusarium spp. can produce this compound in very large amounts, up to 1080 μg per gram of total biomass. However, the primary biological function of fusaric acid is still not fully understood. Numerous studies have attempted to clarify the biological functions of fusaric acid across various species, including virus, fungi, bacteria, mammals, and humans. Several preclinical studies and clinical trials have evaluated its therapeutic potential for human diseases. However, despite these efforts, fusaric acid has not progressed into an approved therapeutic agent, highlighting both its biological complexity and the challenges associated with its clinical development. To date, none of the works have comprehensively enumerated the multifunctional biological roles of fusaric acid and its derivatives. In this review, marking the 90th + anniversary of its discovery, we discuss the most notable roles of fusaric acid across diverse kingdoms of life.