**Background:** Lactoferrin (LF) is an 80 kDa iron-binding glycoprotein of the transferrin family, first discovered in bovine milk. Its structure comprises two homologous globular lobes (N-lobe and C-lobe), each capable of binding one ferric ion (Fe³⁺) with high affinity, even at pH as low as 3.5. LF exists in two conformational states: apo-LF (iron-free) and holo-LF (iron-loaded). LF is one of the most abundant proteins in tear fluid, with concentrations around 1.3–1.84 mg/mL, markedly higher than plasma concentrations (1 μg/mL). It is locally synthesized by the lacrimal gland, corneal epithelial cells, and conjunctival epithelial cells. LF exerts a wide array of biological functions including iron homeostasis regulation, antioxidant protection, anti-inflammatory and immunomodulatory activity, antibacterial, antiviral, antifungal, and anticarcinogenic properties. Its anti-inflammatory effects are mediated through Toll-like receptors (TLR2 and TLR4) and the NF-kB pathway, downregulating proinflammatory cytokines (IL-6, IL-1B, IL-8) and promoting anti-inflammatory cytokines (IL-4, IL-10). Antibacterial activity arises from both iron chelation (bacteriostatic) and direct membrane disruption via cationic charge interaction with bacterial lipopolysaccharides or lipoteichoic acid (bactericidal). Antiviral activity primarily involves binding to host cell surface glycosaminoglycans (heparin sulfate), inhibiting virus-host cell interaction.
**Methods:** This is a narrative review summarizing the molecular structure, biological functions, and ocular surface applications of lactoferrin. The review synthesizes findings from published literature on LF's role in tear fluid, corneal and conjunctival tissues, and its involvement in ocular surface diseases including dry eye disease (DED), infectious keratitis, and keratoconus (KC). The review also covers preclinical studies of LF delivery systems for topical ophthalmic administration.
**Key Results:** In DED, tear LF levels are significantly reduced: 2.11 ± 0.74 mg/mL in normal subjects vs. 1.47 ± 0.76 mg/mL in patients with early dry eye. Reduced tear LF correlates with subjective symptoms and severity of epithelial lesions in Sjögren's syndrome. In HIV-positive patients, tear LF levels were markedly decreased (85.8 mg/dL vs. 156 mg/dL in HIV-negative patients), associated with increased bacterial flora colonization. In KC patients, tear LF levels are 1.54 times significantly lower than controls, and serum LF levels are 2.6 times significantly lower than controls, strongly correlating with disease immune, inflammatory, and clinical status. Preclinical studies of LF delivery systems include: (1) chitosan mucoadhesive nanospheres (crosslinked with TPP or SBE-β-CD) showing mean diameter <300 nm, ζ-potential +17.13 to +19.89 mV, LF immobilization yield ~50%, and in vivo corneal t½ of 114 min (CS/TPP) and 60.5 min (CS/SBE-β-CD) vs. 17.7 min for free molecule; (2) PLGA nanocapsules (50:50 copolymer) with diameters 150–300 nm, encapsulation efficiency >80%, loading capacity up to 60%, and in vivo t½ of 93.31 min (nanospheres) and 51.32 min (nanocapsules); (3) nanostructured lipid carriers (NLC) with mean diameter 120 nm, encapsulation efficiency 80%, loading capacity 70%, and in vivo t½ of 107.82 min and MRT of 141.33 min; (4) hyaluronic acid-coated liposomes with mean size 90.5 nm, ζ-potential +20.5 mV, encapsulation efficiency 50%, showing improved corneal permeation and efficacy in DED animal models; (5) LF-loaded contact lenses (filcon V) loading 61 μg LF per lens, maintaining antioxidant activity in epithelial cell culture.
**Clinical Implications:** LF represents a promising therapeutic target for ocular surface diseases due to its multifunctional properties addressing inflammation, oxidative stress, infection, and iron dysregulation. The consistent finding of reduced tear LF across multiple OSDs supports its potential as a diagnostic biomarker, with commercial development of microfluidic testing (TearScan 300 MicroAssay System) for LF measurement. Topical LF administration could provide a wide spectrum of protection and support existing treatments for DED, ocular infections, and KC. However, significant challenges remain: no topical ophthalmic LF products are on the market, no clinical trials of topical ophthalmic LF are currently registered, only one randomized controlled trial of oral LF-containing supplement for DED has been reported, and long-term safety and efficacy data are lacking. The development of effective LF delivery systems that improve ocular surface permanence and corneal penetration is critical, with nanotechnology-based approaches showing promise in preclinical models. Future directions include establishing consistent animal models for KC, conducting in vivo pharmacokinetic and tissue distribution studies, and advancing to human clinical trials.