The review, led by Samreen Latif and Nauman Khalid of the University of Management and Technology in Lahore alongside colleagues in Pakistan, the United Arab Emirates, and Iran, surveys the current landscape of commercial fortifiers and finds considerable variability. Most products on the market are derived from bovine milk, supplying primarily minerals and macronutrients, while only a handful are formulated from human milk. The compositional differences are striking: reported osmolality of human milk-based formulations ranged from 287 to 393 mOsm/kg, protein content from 0.10 to 2.90 grams, and calcium from 2.62 to 144.9 milligrams per serving. Bovine-based fortifiers raise immunological concerns because of their cow’s milk origin, and thermal processing can alter heat-sensitive proteins, diminishing their resemblance to natural human milk. Human milk-based fortifiers retain a broader spectrum of bioactives, including alpha- and beta-caseins, alpha-lactalbumin, and lysozyme, and a meta-analysis of 681 preterm infants reported lower mortality with human-based compared with bovine-based fortifiers, though rates of necrotizing enterocolitis, sepsis, and retinopathy of prematurity were comparable.

The core problem the review identifies is that many of the most valuable bioactive compounds are fragile. Polyunsaturated fatty acids and fat-soluble vitamins and carotenoids are vulnerable to oxidation during processing and storage, and sensitive components continue to degrade in infant formula. Studies have even suggested that milk fortifiers may increase oxidative stress in premature infants. Encapsulation, the technique of wrapping bioactives in protective shells made from proteins, polysaccharides, or lipids, offers a way to shield these compounds through manufacturing, storage, and the harsh journey of gastrointestinal digestion, then release them where they are needed. Crucially, no single delivery system suits every compound; carrier selection must be tailored to the physicochemical properties of each bioactive.

Lactoferrin, a key antimicrobial protein in human colostrum, illustrates both the promise and the difficulty. It sequesters free iron that bacteria need to grow, destabilizes Gram-negative bacterial membranes, disrupts biofilms formed by Staphylococcus epidermidis on neonatal medical devices, and modulates immune signaling. But it is easily degraded in the gut. Alginate micro-gels achieved encapsulation efficiencies of 68 to 88 percent and better gastric protection than free lactoferrin, though protection varied depending on the iron-binding state of the protein. More sophisticated approaches performed better still: bovine serum albumin–tannic acid multilayer microcapsules delivered 76 to 85 percent gastric protection and, in animal studies, produced 6.5-fold higher bioavailability than free lactoferrin, with measurable accumulation in the liver. Liposomes loaded with lactoferrin showed greater structural stability in infant digestion models than adult ones, and rapeseed phospholipid carriers achieved 91.9 percent encapsulation efficiency with particles under 200 nanometers.

The long-chain fatty acids docosahexaenoic acid and arachidonic acid, critical for brain development and inflammation control, present a different challenge: they oxidize readily and dissolve poorly in water. Clinical trials have shown that supplementing preterm infants with these fatty acids lowered interleukin-6 levels, improved white matter microstructure in the brain, and enhanced linear growth and body composition at three months corrected age. On the encapsulation side, microcapsules built from linear dextrin aggregates achieved 85 percent encapsulation efficiency and strong oxidative protection for DHA, while caseinate–alginate microparticles with a honeycomb structure improved both chemical stability and digestibility. Algae-based DHA with whey protein showed more stable release and higher digestibility than tuna-based versions. Beeswax solid lipid nanoparticles co-delivering DHA, EPA, and vitamin D3 reached encapsulation efficiencies of 86.3 to 92.3 percent and maintained over 90 percent stability under gastric, alkaline, and oxidative stress. For arachidonic acid, coaxial electrospray produced core–shell microcapsules with corn zein walls that reduced odor formation and peroxide levels.

Vitamins A and E, both essential for preterm development, have also attracted encapsulation research. Vitamin A supports surfactant production and fetal lung development, and its deficiency is linked to bronchopulmonary dysplasia, yet vitamin A palmitate is highly prone to oxidation. Coaxial electrospray systems using an OSA-modified starch–maltose shell with an ethyl cellulose core achieved encapsulation efficiency above 98 percent, and adding the amino acid histidine improved oxidative stability up to 214-fold compared with free vitamin A palmitate. Saponin–chitosan complexes extended storage stability to two months with controlled release under acidic conditions. Vitamin E, which modulates inflammatory signaling and may inhibit ferroptosis through its metabolite alpha-tocopherol hydroquinone, has been encapsulated by spray-drying into biopolymer microparticles with efficiencies of 70.1 to 99.4 percent, and nanoencapsulation increased the bioavailability of tocotrienols at least five-fold.

Probiotics add another dimension. Specific strains of Bifidobacterium and Lactobacillus exclude pathogens through competitive exclusion, produce antimicrobial compounds such as short-chain fatty acids and bacteriocins, and have been associated with reduced necrotizing enterocolitis and late-onset sepsis and shorter hospital stays in preterm infants. Keeping these live organisms viable through drying, storage, and digestion is the central technical hurdle. Mixed-flow spray drying achieved 81 percent survival, outperforming freeze drying, while Maillard reaction conjugates of soy protein isolate and carrageenan protected bacteria through pasteurization and simulated digestion. Whey protein with xanthan gum coating shielded cells against gastric acid, bile, and heat, and yeast encapsulated in whey protein–chitosan matrices reached roughly 91 percent encapsulation efficiency with up to 95 percent survival during storage.

Caseins occupy a unique position: rather than being encapsulated themselves, they serve as carrier matrices for other bioactives. Casein micelles protected beta-carotene through industrial sterilization processes including heating, pasteurization, and high-pressure processing, and casein–guar gum blends enhanced the photostability and antioxidant capacity of encapsulated beta-carotene. Casein walls also improved the oxidative stability and shelf life of fish oil destined for infant formula, and loading vitamin D2 into sodium caseinate increased its in vitro bioaccessibility. Because casein and spray-drying are already standard in dairy manufacturing, these carriers may be among the most commercially feasible routes to fortified products, though the review stresses that existing studies measured processing stability or in vitro bioaccessibility rather than neonatal tolerance.

Despite this impressive laboratory progress, the review’s authors are emphatic that the field remains far from the neonatal bedside. No clinical trial has assessed encapsulated lactoferrin, probiotics, carotenoids, or vitamins in human milk fortifiers, and most encapsulation data come from experimental food systems rather than studies designed for preterm infants. Safety questions loom large: the intestinal barrier of infants under 33 weeks’ gestation remains immature and permeable in the first weeks of life, raising concerns about how nanosized carriers behave, and a documented case of severe cow’s milk allergy triggered by a bovine-derived fortifier underscores the immunological risks of protein-based matrices. Osmolality is another practical barrier, since multicomponent fortifiers raised donor milk osmolality by 54.6 to 109.1 mOsm/kg within two minutes of addition. Regulation adds further friction: neither the FDA nor EFSA has specific frameworks for encapsulated ingredients in foods, many countries lack nanomaterial rules entirely, and numerous promising carriers lack GRAS approval for infant use. The authors call for biocompatible carrier materials, compatibility testing in actual fortified human milk, and carefully designed neonatal clinical trials before encapsulated bioactives can routinely reach the smallest and most vulnerable patients.

Subject of Research: Encapsulation of bioactive compounds to improve the delivery and stability of human milk fortifiers for preterm and low birth weight infants

Article Title: Recent trends in encapsulated bioactives for improving the delivery of infant milk fortifiers

Article References: Latif, S., Naseer, M. S., Khalid, N., & Sarabandi, K. (2026). Recent trends in encapsulated bioactives for improving the delivery of infant milk fortifiers. Food Science of Animal Resources, 46(1), Article 107. https://doi.org/10.1007/s44463-026-00114-4

Image Credits: AI Generated

DOI: 10.1007/s44463-026-00114-4

Keywords: human milk fortifiers, preterm infants, encapsulation, lactoferrin, DHA, arachidonic acid, probiotics, vitamin A, vitamin E, carotenoids, neonatal nutrition, GRAS carriers