important for veterinary applications involving food-producing animals. Unlike conventional small-molecule
anthelmintics, nanoformulations may exhibit altered tissue distribution, prolonged retention, and formulation-
dependent drug release, which can influence the depletion of active compounds and nanoparticle-associated
components from edible tissues. Consequently, nanoparticles or their associated drug residues may potentially
persist in tissues such as muscle, liver, kidney, and fat and, in lactating animals, may also be transferred into
milk, raising concerns regarding consumer exposure. However, the extent of such accumulation and persistence
is highly dependent on nanoparticle composition, particle size, surface characteristics, route of administration,
dose, and the physicochemical properties of the encapsulated drug. Therefore, residue depletion cannot be
reliably extrapolated from conventional formulations of the same anthelmintic. Dedicated pharmacokinetic and
tissue-residue studies in relevant livestock species are required to characterize absorption, distribution,
transformation, and elimination and to determine the persistence of both the active pharmaceutical ingredient
and relevant nanoparticle-derived components. Such data are essential for establishing scientifically justified
maximum residue limits (MRLs) and appropriate withdrawal periods for meat, milk, and other edible products
before nano-anthelmintic formulations can be routinely used in food-producing animals. Regulatory evaluation
should therefore consider formulation-specific pharmacokinetic, residue-depletion, toxicological, and
consumer-safety data, particularly where repeated administration or prolonged tissue retention is anticipated.
The safety of nanomedicine also requires careful evaluation. Parameters such as biocompatibility,
biodegradability, pharmacokinetics, nanotoxicology, large-scale manufacturing, and regulatory compliance
must be thoroughly assessed before clinical application.
[234]
Certain metallic nanoparticles have been reported
to accumulate in the liver and other reticuloendothelial tissues, resulting in elevated liver enzyme levels and
tissue damage following prolonged exposure.
[235]
Furthermore, the toxicity of metallic nanoparticles often
depends on their composition, particle size, surface chemistry, and solubility, with highly soluble metal
nanoparticles generally exhibiting greater cytotoxicity in vitro.
[236]
Therefore, balancing therapeutic efficacy
with long-term safety remains a critical challenge for future nano-anthelmintic development. Overall,
nanotechnology provides a versatile platform for overcoming many of the limitations associated with
conventional anthelmintic therapy. Nanoformulations can enhance drug solubility, stability, bioavailability, and
targeted delivery while minimizing systemic exposure and adverse effects. By increasing drug accumulation at
parasite-infected tissues, including the gastrointestinal tract, liver, lungs, and skin, nanoparticle-based
formulations have the potential to improve treatment outcomes, reduce the emergence of resistance, and
revitalize the therapeutic efficacy of existing anthelmintic drugs.
[144]
Continued advances in nanocarrier design,
safety evaluation, and clinical translation are expected to establish nanomedicine as an important component
of future strategies for managing helminth infections.
2.5 Drug delivery via extracellular vesicles and lipid-based nanocarriers
Efficient drug delivery remains one of the major challenges in the treatment of helminth infections.
Conventional anthelmintic drugs often exhibit poor aqueous solubility, limited bioavailability, rapid systemic
clearance, and nonspecific tissue distribution, reducing their therapeutic efficacy. Consequently, considerable
attention has been directed toward vesicular drug delivery systems, including extracellular vesicles (EVs),
liposomes, lipid nanoparticles (LNPs), and solid lipid nanoparticles (SLNs), which offer improved drug stability,
controlled release, targeted delivery, and reduced systemic toxicity. Extracellular vesicles are naturally
occurring nanosized membrane-bound particles released by both prokaryotic and eukaryotic cells. Helminths
also secrete EVs as components of their excretory/secretory products, thereby enabling them to communicate
with host cells and modulate immune responses by transferring proteins, lipids, messenger RNAs, and
microRNAs.
[237,238]
Beyond their biological role in host–parasite interactions, EVs have attracted considerable
interest as naturally derived drug-delivery vehicles owing to their excellent biocompatibility, low
immunogenicity, and inherent ability to transport bioactive molecules across biological barriers. These
characteristics make EVs promising candidates for therapeutic delivery, vaccine development, and diagnostic
applications in parasitic diseases. Among lipid-based nanocarriers, liposomes remain one of the most
extensively investigated drug delivery systems. Liposomes are biodegradable phospholipid bilayer vesicles
capable of encapsulating both hydrophilic and hydrophobic therapeutic agents, thereby protecting drugs from
enzymatic degradation and improving their pharmacokinetic properties.
[239,240]
Their structural similarity to
biological membranes facilitates cellular uptake and prolongs systemic circulation, while surface modification
with antibodies, peptides, or receptor-specific ligands enables targeted drug delivery to diseased tissues.
Consequently, liposomal formulations have been widely investigated for improving the efficacy and safety of
anticancer, antiviral, antibacterial, and antiparasitic therapies.
In helminth infections, liposomal drug delivery has shown considerable promise for enhancing the therapeutic
performance of existing anthelmintic agents. Encapsulation of praziquantel and ivermectin within liposomes
has been reported to improve drug delivery, prolong drug release, and increase deworming efficacy compared
with conventional formulations.
[237]
Interestingly, phospholipid-rich liposomes themselves may also exert
direct effects on parasites by altering the motility and morphology of Schistosoma mansoni. At the same time,