Pharmacokinetic and Delivery Challenges of Peptides and Oligonucleotides
Nanocarriers for Peptide and Oligonucleotide Delivery
Therapeutic Applications of Nanocarriers for Delivering Peptides and Oligonucleotides
Conclusion and Future Perspectives
References and Further Reading
Nanocarriers are making it possible to use some of medicine’s most precise yet most fragile molecules effectively. By packaging therapeutic peptides and gene-targeting oligonucleotides into engineered nanoparticles, researchers can protect them from rapid breakdown in the body, improve their circulation, and concentrate delivery at the intended site. In doing so, nanocarriers hurdle a predominant barrier to getting these drugs into the clinic.
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Peptides and oligonucleotides, often grouped together as TIDES, are increasingly seen as powerful therapeutic tools.2 Their high specificity, tunable biological activity, and ability to modulate targets inaccessible to traditional small molecules distinguish them from conventional therapies.
Peptides work by mimicking, or blocking, the body's own proteins, giving clinicians a way to influence cellular signalling with fine control. Oligonucleotides have a different approach. They can 'dial' gene activity up or down at the transcriptional or post-transcriptional level, making their genetic intervention more targeted.
Bioactive peptides have a demonstrable track record in cancer therapy, drug screening, and more. They have both shown clinical benefit across many diseases, such as genetic and rare conditions.
The growing number of regulatory approvals for TIDES, including the four new drugs sanctioned by the Food and Drug Administration (FDA) in 2024, highlights how quickly this field moves.2
Pharmacokinetic and Delivery Challenges of Peptides and Oligonucleotides
Despite their high selectivity and low toxicity, both peptides and oligonucleotides have some stubborn problems in practice. Perhaps the most significant is stability in vivo. Peptides are prone to breakdown by proteases, while oligonucleotides are easily cut by nucleases. Because these enzymes are prolific in blood, the gastrointestinal tract, and tissue, many therapies using peptides and oligonucleotides can have short half-lives with reduced efficacy.3
Beyond instability, the physicochemical characteristics of peptides and oligonucleotides, including substantial molecular size, marked hydrophilicity, and significant charge, impede efficient membrane permeation and result in poor bioavailability.4 This limits bioavailability, restricts access to intracellular targets, and makes it harder for them to reach useful concentrations at the site of action.
This is why so much current research centers on two priorities: improving molecular stability (often through chemical modification) and developing smarter delivery systems that can enhance pharmacokinetics, improve tissue targeting, and minimize immunogenic responses.
Nanocarriers for Peptide and Oligonucleotide Delivery
Nanocarriers are designed to do what these therapies struggle to do alone: survive the journey and arrive intact. By helping drugs cross biological, physical, and chemical barriers, these systems can meaningfully improve both efficacy and safety.
Encapsulation is one such method. Packing peptides or oligonucleotides inside nanoparticles like this creates a protective shell against enzymatic attack, increasing stability, and allowing controlled release over time. In practice, that means better pharmacokinetics and a stronger chance of the drug doing its job before it degrades.5,6
Scientists can also engineer nanocarriers to target specific tissues or disease sites, such as tumors. By modifying the surface of nanoparticles with targeting molecules, these systems can navigate physiological barriers more efficiently and deliver the therapeutic payload precisely at the target site, reducing off-target effects.
Delivery route also matters. Depending on the therapy, nanocarriers may be administered subcutaneously, intravenously, or even orally. The best choice depends on the disease, how fast the drug needs to be released, and which biological barriers must be crossed.7
Therapeutic Applications of Nanocarriers for Delivering Peptides and Oligonucleotides
Researchers have designed numerous nanocarriers for the safe and targeted delivery of peptides and oligonucleotides to address a wide range of diseases. Some of the key therapeutic applications are discussed below:8
Cancer Therapy: Nanocarriers such as PLGA nanoparticles, liposomes, micelles, and gold nanoparticles deliver tumor-targeting peptides, such as arginine-glycine-aspartic acid, and oligonucleotides, including small interfering RNA (siRNA), microRNA (miRNA), and antisense oligonucleotides targeting oncogenes.
These systems have shown promise in treating cancers such as breast cancer, prostate cancer, and glioblastoma by enhancing drug stability, targeting, and efficacy.
Neurodegenerative Diseases: PLGA nanoparticles, liposomes, nanoemulsions, and micelles deliver neuroprotective peptides, amyloid-beta-inhibitory peptides, siRNA, and antisense oligonucleotides targeting amyloid and tau proteins to improve cognitive function.
Tissue Regeneration and Bone Repair: Hydrogels and chitosan nanoparticles deliver bioactive peptides, such as bone morphogenetic proteins (BMPs), collagen mimetics, and neural repair peptides, as well as oligonucleotides (siRNA, miRNA) to enhance bone, vascular, and neural repair.
Infectious Diseases and Vaccines: Nanocarriers such as liposomes, solid lipid nanoparticles, and nanoemulsions deliver antimicrobial peptides (e.g., melittin) and vaccine peptides to boost immunity and fight difficult infections.
Wound Healing: Liposomes, PLGA nanoparticles, chitosan nanoparticles, and peptide-based hydrogels deliver antimicrobial, angiogenic, and collagen-mimetic peptides, as well as siRNA and miRNA, to modulate inflammation and promote tissue repair, accelerating wound closure and regeneration.
Gene Delivery and Genetic Therapy: Dendrimers, cationic polymers, lipid nanoparticles, and peptide-oligonucleotide nanohybrids functionalized with cell-penetrating peptides deliver oligonucleotides, including plasmid DNA, siRNA, miRNA, antisense oligonucleotides, and CRISPR/Cas9 guide RNAs.
These systems enable precise gene editing, antisense therapy, and treatment of genetic disorders.
Read this article to learn more about precision chemistry in peptide and oligonucleotide synthesis.
Conclusion and Future Perspectives
Nanocarriers have reshaped the prospects for peptide and oligonucleotide medicines by protecting these sensitive macromolecules and improving uptake into target cells. Their potential stretches across cancers, neurodegenerative disorders, infections, autoimmune diseases such as rheumatoid arthritis, and regenerative medicine.
Despite these advances, scientists have highlighted several challenges, including immune responses, off-target effects, and complexities in large-scale manufacturing, that hinder the full clinical potential of nanocarrier-based delivery systems.
A better understanding of nanocarrier interactions with biological systems and advances in nanotechnology will support the clinical translation of these systems, potentially enabling more effective and personalized treatments for complex diseases.
References and Further Reading
- Zhu C, Mu J, Liang L. Nanocarriers for intracellular delivery of proteins in biomedical applications: strategies and recent advances. J Nanobiotechnology. 2024;22(1):688. doi: 10.1186/s12951-024-02969-5.
- Al Musaimi O, et al. 2024 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals (Basel). 2025;18(3):291. doi: 10.3390/ph18030291.
- Tasdemiroglu Y, Gourdie RG, He JQ. In vivo degradation forms, anti-degradation strategies, and clinical applications of therapeutic peptides in non-infectious chronic diseases. Eur J Pharmacol. 2022;932:175192. doi: 10.1016/j.ejphar.2022.175192.
- Al Tahan MA, et al. Oral peptide delivery Systems: Synergistic approaches using polymers, lipids, Nanotechnology, and needle-based carriers. J Drug Deliv Sci Technol. 2025; 112, 107205. https://doi.org/10.1016/j.jddst.2025.107205
- Zhang X, Li X, Zhao Y, Zheng Q, Wu Q, Yu Y. Nanocarrier system: An emerging strategy for bioactive peptide delivery. Front Nutr. 2022;9:1050647. doi: 10.3389/fnut.2022.1050647.
- Alsaidan OA. Nanocarriers: Exploring the Potential of Oligonucleotide Delivery. Curr Drug Deliv. 2025;22(7):895-920. doi: 10.2174/0115672018306882240618093152.
- Zeb A, et al. Potential and Applications of Nanocarriers for Efficient Delivery of Biopharmaceuticals. Pharmaceutics. 2020; 12(12):1184. https://doi.org/10.3390/pharmaceutics12121184
- Omidian H, Wilson RL, Castejon AM. Recent Advances in Peptide-Loaded PLGA Nanocarriers for Drug Delivery and Regenerative Medicine. Pharmaceuticals. 2025; 18(1):127. https://doi.org/10.3390/ph18010127
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