Plain Language Summary
Standard nutritional supplements are poorly absorbed and quickly cleared from the body, but encapsulating them in nanoscale lipid particles (nanoliposomes) consistently improves their stability and absorption by two- to ten-fold in laboratory models. Targeting these particles to specific organs or organelles - including mitochondria using peptides like SS-31 - has shown protective effects in preclinical models of heart disease, kidney injury, and neurodegeneration. The main barriers to clinical use are the difficulties of manufacturing at scale, cost, and managing immune reactions to the particle coating.
Abstract
Conventional nutritional supplements frequently demonstrate limited clinical effectiveness due to the harsh milieu of the gastrointestinal tract, inefficient trans-epithelial transport, and rapid systemic clearance. Nanoliposomal delivery platforms - lipid bilayer vesicles on the nanometer scale - have attracted attention as an adaptive strategy to shield sensitive nutrients, navigate biological barriers, and deliver payloads directly to target tissues or even sub-cellular organelles. Despite a growing body of literature, a consolidated appraisal of design principles, targeting modalities, and translational hurdles is still needed to guide future nutraceutical innovation. We aim to: (1) Summarize the physicochemical foundations of nanoliposomal nutrient carriers; (2) Delineate state-of-the-art approaches for organ-specific and organelle-specific targeting, with particular emphasis on renal and mitochondrial delivery; (3) Evaluate current evidence supporting therapeutic benefits in cardiometabolic, neuroprotective, and renal-repair contexts; and (4) Map unresolved challenges - including manufacturing scale-up, cost, and regulatory oversight - to inform a roadmap for clinical translation. A systematic literature search was performed across PubMed, Web of Science, and Scopus through May 2025 using Boolean combinations of "nanoliposome", "nutrient", "targeted delivery", "bioavailability", and organ-specific terms (, "kidney", "mitochondria"). Primary research articles, systematic reviews, and relevant meta-analyses written in English were included. Data were extracted on liposomal composition, particle size, surface modifications (, polyethylene glycol, ligand conjugation),andbio-distribution, efficacy outcomes, and safety profiles. Key design variables were mapped against reported biological performance to identify convergent principles. Sixty-four original studies and twenty-one reviews met inclusion criteria. Encapsulation within phosphatidylcholine-rich bilayers consistently enhanced nutrient stability in simulated gastric fluid and improved Caco-2 trans-epithelial transport two-fold to ten-fold compared with free compound controls. Ligand-mediated strategies - such as folate, lactoferrin, or peptide conjugation - achieved organ-specific accumulation, with kidney-directed liposomes demonstrating up to a four-fold increase in renal cortex uptake. Mitochondrial targeting using amphipathic peptides (, SS-31) or triphenylphosphonium moieties delivered antioxidant nutrients to the organelle, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) in preclinical cardiomyopathy and neurodegeneration models. Endosomal escape was most effectively triggered by fusogenic lipids (, dioleoylphosphatidylethanolamine) or pH-responsive polymers. PEGylation prolonged circulation half-life by 3-6 hours but elicited anti-polyethylene glycol antibodies in approximately one-quarter of recipients; emerging natural sterol-mimetic or collagen-mimetic coatings showed comparable stealth behavior with superior biodegradability. Scalability remains limited: Only three studies reported pilot-scale (> 10 L) batches with Good Manufacturing Practice-compliant reproducibility. Targeted nanoliposomal systems substantially improve nutrient stability, absorption, and tissue specificity, offering a credible route to transform supplement efficacy for cardiometabolic, renal, and neuroprotective indications. Optimization of lipid composition, escape mechanisms, and biocompatible surface chemistries can further enhance therapeutic indices. Nonetheless, industrial-scale manufacturing, cost containment, and immunogenicity mitigation remain critical obstacles. Addressing these gaps through standardized characterization protocols, head-to-head clinical trials, and biomaterial innovation will be essential to unlock the full potential of nanoliposomal nutraceuticals in routine healthcare practice.