Therapeutic Peptides in Action: A Comprehensive Review of Delivery Technologies and Biomedical Applications along with Future Perspectives

 

Dr. M. Sunitha Reddy, Dr. K. Anie Vijetha, Vaishnavi Bakka* 

Department of Pharmaceutics, Centre for Pharmaceutical sciences, University college of engineering, science and technology JNTUH, Kukatpally, Hyderabad, 500085

*Correspondence: vaishnavireddybakka1@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2025.4910       

Article Information		Abstract
Review Article Received: 26/09/2025 Accepted: 29/09/2025 Published: 30/09/2025   Keywords Peptide drug conjugates; cell-penetrating peptides; self-assembling peptides; nanoparticle functionalization;  drug delivery; targeted therapy.		Peptides are short chains of amino acids they possess unique properties such as their diversity in structure, tunable Hydrophobicity/Hydrophilicity and their inherent Bio compatibility.   Peptide-based drug delivery systems (PBDDS) have emerged as versatile systems bridging small molecules and biologics. Over the last decade, innovations in peptide chemistry, self-assembly, conjugation strategies, and targeting strategies have transformed peptides from passive excipients used into active delivery vehicles. This review focuses on peptide drug conjugates (PDCs), cell-penetrating peptides (CPPs), self-assembled nanostructures, hybrid nanoparticles and hydrogels. Also gives an insight on transitional challenges including stability and immunogenicity, including Opportunities in AI-guided peptide design, oral/transmucosal delivery.

 

Fig1: Graphical Abstract

INTRODUCTION

Peptides are short chains of amino acids they possess unique properties such as structural diversity, tunable hydrophobicity or hydrophilicity, sequence programmability, and inherent biocompatibility.[1] Historically they were used primarily as hormones or signalling molecules. Now peptides serve dual roles as therapeutics themselves and as building blocks or targeting ligands in drug delivery systems.  When compared to antibodies, peptides are smaller in size, possess lower immunogenicity, and are simpler, can be synthesized via solid-phase peptide synthesis (SPPS).[2] Their conformational flexibility allows integration with small molecules, biologics, and nanomaterials.

However, in early times peptide delivery systems had limitations such as.[3]

·         Rapid proteolytic degradation

·         Renal clearance

·         Poor membrane permeability

Over the last decade, advances in chemistry and nanotechnology have transformed these liabilities into opportunities. Strategies like cyclization, D-amino acid substitution, PEGylation, and lipidation now improve peptide stability. Meanwhile, conjugation to drugs or nanoparticles enhances pharmacokinetics and tissue targeting.[4]

Emerging modalities like mRNA vaccines, gene editing tools, and protein therapeutics have further driven the need for sophisticated delivery systems. [5]

HISTORY

1.Early Peptide Therapeutics (1920s-1950s)

The earliest use of peptides in medicine goes to the discovery of insulin in 1921 by Banting and Best, demonstrating the potential of peptides to revolutionize medicine.[6] Followed by peptide hormones such as oxytocin and vasopressin were identified and used clinically.[7] However, these early peptides faced significant delivery challenges like poor oral bioavailability, short half-life, and susceptibility to enzymatic degradation.

2.Synthetic Breakthroughs and Chemical Modifications (1960s–1980s)

The invention of solid-phase peptide synthesis (SPPS) by Merrifield in 1963[8] provided a scalable method for producing peptides. These advance allowed researchers to explore peptides beyond natural hormones. Chemical modifications such as PEGylation (polyethylene glycol conjugation) emerged in the 1970s, significantly extending circulation half-lives of peptides and proteins. [9]

3.Targeting and Penetrating Peptides (1980–2000) [10,11]

In the late 20th century, two revolutionary discoveries redefined peptide use in drug delivery:

•       RGD Motifs: Ruoslahti and colleagues identified the Arg–Gly–Asp (RGD) sequence as a ligand for integrins, enabling cell-specific targeting of peptides and peptide-functionalized nanoparticles.

•       Cell-Penetrating Peptides (CPPs): In the 1980s and 1990s, the HIV-1 trans-activator of transcription (TAT) protein was shown to cross membranes, with its basic domain later identified as a transferable cell-penetrating peptide.

•       By the late 1990s, peptides were recognized not only as therapeutics but as targeting ligands and carriers.

4.Emergence of Peptide-Based Carriers (2000–2010)

In the early 2000s, peptide self-assembly was harnessed to create drug delivery vehicles. The RADA16 peptide was among the first self-assembling peptides to form nanofibers and hydrogels for drug encapsulation and tissue engineering.[12] During this time, peptide–drug conjugates (PDCs) were proposed as smaller, more penetrant alternatives to antibody–drug conjugates (ADCs).[13] Simultaneously, systematic work on CPPs expanded, leading to mechanistic understanding of endocytosis-mediated uptake and endosomal escape. [14]

5.Peptides in Integration with Nanotechnology (2010–2020) [15,16,17]

•           Advances in chemistry and nanotechnology enabled hybrid systems like lipid, polymeric, or inorganic nanoparticles decorated with targeting or penetrating peptides

•           Stimuli-responsive linkers (pH-sensitive, enzyme-cleavable) for controlled drug release in peptide drug conjugates

•           Multifunctional self-assembling peptides that respond to tumor microenvironment conditions (low pH, redox states)

•           Peptide-functionalized nanoparticles (lipid, polymeric, gold, and quantum dots) for targeted delivery and theranostics

•           During this period, peptides also began entering clinical trials as delivery motifs, with oncology applications at the forefront.

6.Modern Era of Peptides (2020–2025) [18,19,20,21]

•   The last five years have marked a turning point:

•   The approval of melflufen, a peptide drug conjugate, for multiple myeloma.

•   Widespread use of lipid nanoparticles (LNPs) in mRNA vaccines highlighted peptides’ potential to enhance targeting and endosomal escape.

•   AI-driven peptide design (including AlphaFold-based structural predictions) enabled rational development of stable, non-immunogenic, multifunctional peptides.

•   Theranostic peptides combining imaging and therapy advanced toward precision medicine applications.

PEPTIDE–DRUG CONJUGATES (PDCS) [22]

By covalently linking a therapeutic load to a peptide carrier, PDCs improve solubility, stability, and tissue targeting. This approach parallels antibody drug conjugates (ADCs) but offers advantages such as smaller size for better tumor penetration, tunable pharmacokinetics, and easier synthesis.

A. Linkers in PDC

In PDCs, linkers are the essential connections between medications and peptides, greatly affecting the stability and duration of their circulation in vivo. When a linker reaches the target tissue, it should be able to release the drug quickly and effectively while remaining stable throughout circulation to avoid premature release. Additionally, neither the drug's action nor the peptide's affinity for its receptor should be affected by the linker.

a)         Enzyme-sensitive linkers: In PDCs, enzyme-sensitive linkers are essential because they allow for targeted drug release in response to particular enzymatic activity. Chemical bonds or peptide sequences that preferentially break down when enzymes are present are frequently the basis for these linkers. Since esterases and amidases are abundant in tumor cell endosomes and lysosomes and aid in drug release, chemical linkages including ester, amide, and carbamate are frequently used in PDC designs. Among these, amide and ester linkages are very often used to create tumour-targeted PDCs. Comparably, carbamate linkers are prized for their stability and capacity for trace-free hydrolysis, which upon drug release yields carbon dioxide, amines, and alcohols, guaranteeing effective delivery free of residual fragments.[23]

b)         pH-sensitive linkers: By taking advantage of the acidic circumstances of the tumor microenvironment (pH 6.5–6.9) in contrast to the normal blood pH (7.2–7.4), pH-sensitive linkers allow for precisely targeted medication release at the tumor location. Because these linkers break down quickly in acidic environments while remaining stable in circulation, medications are delivered primarily inside the tumor. Hydrazone bonds are the most researched of the several pH-sensitive linkers because of their acidity sensitivity and efficiency in establishing targeted medication administration. [24]

c)         Redox-responsive linkers: In redox-sensitive drug delivery systems, glutathione (GSH), a strong intracellular reducing agent, is essential. GSH is especially prevalent in tumor cells because of their hypoxic and aberrant microenvironment, which increases reductase activity and raises GSH levels. Intracellular concentrations of GSH are roughly 1000 times higher than extracellular levels. Because of this particular feature of tumor cells, GSH is an essential catalyst for the cleavage of particular chemical bonds found in drug conjugates. Notably, GSH's antioxidant qualities allow it to break down metal-thiol junctions, thioesters, disulfides, and other linkages, allowing for targeted medication release.[25]

A.        Theranostic PDCs [26,27]

Theranostics combine therapy and diagnostics in one construct. Recent examples integrate imaging agents such as near-infrared fluorophores or radioisotopes into PDCs. An injectable theranostic formulation for breast cancer was created by Khan et al. employing polyethyleneimine-coated up conversion nanoparticles (UCNP) electro spun with an EGFR-targeting peptide and coupled with the anticancer medication DOX. Under 980 nm irradiation, the UCNP, which measured 26.75 ± 1.54 nm, produced a considerable amount of heat (~62.7 °C in 5 min) and showed a photothermal conversion efficiency of 68.8%. The system demonstrated encapsulation efficiency (98.74%) and high drug loading (54.56%), with pH-responsive drug release in acidic environments. In breast cancer cell lines, it demonstrated outstanding biocompatibility and antitumor solid effects. It is thought to produce reactive oxygen species to encourage apoptosis. This tailored formulation, when combined with photothermal therapy, provides improved cancer treatment with reduced toxicity.[28]

B.        RGD-based PDCs

RGD conjugates remained popular for tumor targeting. In 2017, Zhang et al. developed a doxorubicin–RGD conjugate showing superior tumor accumulation and reduced cardiotoxicity compared to free doxorubicin.[29] By 2023, improved multivalent RGD constructs enhanced binding avidity and facilitated integrin clustering for receptor-mediated endocytosis.[30]

C.        Somatostatin analog PDCs

Somatostatin receptor (SSTR) targeting has seen clinical traction. A 2020 study by Li et al. used an octreotide camptothecin conjugate, achieving selective killing of neuroendocrine tumor cells in xenografts.[31] In 2024, an optimized linker improved plasma stability, leading to Phase II trials. [32]

Pharmacokinetics and biodistribution

Pharmacokinetics (PK) can be tuned by altering peptide length, charge, and hydrophobicity. PEGylation prolongs circulation half-life by reducing renal clearance. [33]

Challenges for PDCs

•      Immunogenicity: Repeated dosing may elicit anti-peptide antibodies [34].

•      Scale-up: Solid-phase synthesis of long or complex peptides can be costly [35].

•      Heterogeneous tumor receptor expression: Tumor heterogeneity may limit efficacy of single-target peptides [36].

CELL-PENETRATING PEPTIDES (CPPS) [37]

CPPs are short cationic or amphipathic peptides that traverse biological membranes, enabling the intracellular delivery of diverse cargos like proteins, nucleic acids, and nanoparticles. Their small size and relative ease of synthesis make them attractive alternatives to viral vectors or lipid-based carriers.

Classification:

CPPs are broadly classified as:

i.          Cationic CPPs: Cationic CPPs provide a net positive charge at physiological pH and exhibit a high affinity for penetrating cells without requiring interaction with receptors. They are rich in arginine or lysine (e.g., TAT, penetration).

ii.         Amphipathic CPPs: contain hydrophilic and hydrophobic segments, The hydrophilic area can be inserted into the hydrophobic lipid head groups by the interaction of nonpolar residues like alanine (A), leucine (L), isoleucine (I), glycine (G), and valine (V). The majority of CPPs, both synthetic and natural, use polarity differences to pass through the cell membrane and enter the cell.

iii.        Anionic CPPs: Anionic CPPs with a negative charge are a different type of amphipathic CPP. Differently from their cationic counterpart, these peptide chains target and enter the cells.

iv.        ADVANCES IN CPP [38,39]

•           Cyclization and D-amino acid substitution: Enhances protease resistance without sacrificing activity.

•           pH- and enzyme-responsive CPPs: Trigger cargo release in specific environments (e.g., tumor acidic pH).

SELF-ASSEMBLING PEPTIDE NANOSTRUCTURES

Self-assembling peptides spontaneously organize into nanostructures such as nanofibers, nanotubes, micelles, or vesicles under physiological conditions.[39] These nanostructures serve as drug reservoirs, scaffolds for tissue engineering or carriers for controlled release.

•           β-sheet forming sequences (e.g., RADA16) that form stable nanofibers

•           α-helical or amphiphilic peptides that assemble into micelles or vesicles

•           π–π stacking sequences for enhanced stability and stimuli-responsiveness

a)         Stimuli-responsive self-assembly

Recent research focuses on controlling assembly/disassembly via pH, temperature, or enzymatic cues

b)         Hybrid self-assembling systems

Combining peptides with polymers or inorganic components enhances mechanical stability and function.

LIPID-BASED NANOPARTICLES FUNCTIONALIZED WITH PEPTIDES

         Targeted Lipid Nanoparticles (LNPs)[40]

LNPs encapsulate nucleic acids, hydrophobic drugs, or proteins in lipid bilayers. Their limitations include poor tissue specificity and rapid clearance by the reticuloendothelial system (RES). LNPs with peptides solves these issues.

•           RGD-modified LNPs: Used for tumor angiogenesis targeting via integrin αvβ3 binding, increasing tumor accumulation in glioblastoma and melanoma models

•           Angiopep-2–LNPs: Engineered to cross the blood-brain barrier (BBB) by binding LRP1 receptors, enabling delivery of siRNA and doxorubicin to brain tumors

•           Hepatocyte-targeting peptides: Applied in siRNA-based therapies for liver diseases, providing alternatives to GalNAc conjugation.

POLYMERIC NANOPARTICLES FUNCTIONALIZED WITH PEPTIDES

         PLGA–Peptide Hybrids [41,42,43]

Poly (lactic-co-glycolic acid) (PLGA) is FDA-approved but lacks targeting ability. Conjugating PLGA nanoparticles with tumor-homing peptides significantly improves therapeutic outcomes:

•           PLGA–RGD nanoparticles showed enhanced doxorubicin delivery and reduced cardiotoxicity

•           PLGA–NGR formulations successfully targeted tumor vasculature in colon carcinoma xenografts

         PEG-Peptide Systems

PEGylation prolongs circulation but reduces cellular uptake (“PEG dilemma”). Peptides overcome this by restoring receptor-mediated uptake:

•           PEG–RGD nanoparticles enhanced paclitaxel uptake in ovarian cancer models.

•           PEG–CPP hybrids provided efficient systemic delivery of antisense oligonucleotides.

         Stimuli-Responsive Polymeric Hybrids

Polymeric nanoparticles conjugated with peptides can be engineered for stimuli-responsive release:

•           pH-sensitive CPP–PLGA hybrids for endosomal escape.

•           MMP-cleavable RGD–polymeric micelles for tumor microenvironment-triggered drug release.

8.         INORGANIC NANOPARTICLES WITH PEPTIDE [44]

a.         Gold Nanoparticles (AuNPs): AuNPs have tunable sizes and surfaces, ideal for functionalization.

1.         CPP–AuNP conjugates delivered siRNA to hepatocytes with high efficiency.

2.         RGD–AuNPs enabled photothermal therapy by improving selective tumor accumulation.

b.         Quantum Dots (QDs): Functionalized QDs are powerful imaging tools. Peptide decoration improves biocompatibility and targeting.

c.         Magnetic Nanoparticles (MNPs): Magnetic nanoparticles decorated with peptides are used for targeted drug delivery and MRI imaging.

9.         PEPTIDE HYDROGELS AND DEPOT SYSTEMS [45,46,47,48,49]

Peptide hydrogels are networks of self-assembled peptides forming injectable or implantable depots. They mimic extracellular matrices, offering tunable porosity, biodegradability, and drug release kinetics. Hydrogels are particularly suitable for:

•           Localized cancer therapy (sustained release near tumor sites).

•           Wound healing and regenerative medicine (biocompatible scaffolds).

•           Vaccine delivery depots (slow release of antigens and adjuvants).

MECHANISMS OF HYDROGEL FORMATION

Hydrogel formation relies on:

•           β-sheet peptides (e.g., RADA16) forming fibrillar networks.

•           Ionic complementary peptides where alternating charged residues drive assembly.

•           Enzyme-triggered assembly for in situ gelation at target sites.

•           pH/temperature responsive motifs for on-demand gelling.

APPLICATIONS

a)         Localized Chemotherapy Depots

A β-sheet hydrogel loaded with doxorubicin released drug over 21 days in breast cancer xenografts, reducing systemic toxicity

Injectable peptide–paclitaxel gels provided superior tumor regression compared to intravenous delivery

b)         Combination Therapies

Hydrogels co-delivering doxorubicin and immune checkpoint inhibitors enhanced synergistic antitumor responses.

Multifunctional hydrogels integrating photothermal peptides + chemotherapeutics enabled spatiotemporal therapy.

c)         Regenerative Medicine and Wound Healing

Hydrogels provide scaffolds for tissue repair:

Self-assembling hydrogels seeded with mesenchymal stem cells accelerated bone regeneration.

Antimicrobial peptide hydrogels prevented infection in burn wounds.

d)         Vaccines and Immunotherapy

Peptide hydrogels serve as depots for antigen/adjuvant co-delivery:

A 2020 hydrogel releasing peptide antigens + CpG adjuvant enhanced dendritic cell maturation.

Hydrogel-based SARS-CoV-2 subunit vaccines induced strong mucosal and systemic immunity in mice.

Combination hydrogel systems with cancer antigens achieved long-lasting T-cell memory.

PROTEOLYTIC STABILITY AND PHARMACOKINETICS [50,51]

One of the most persistent challenges for peptide-based delivery systems is instability in vivo. Peptides are readily degraded by proteases in plasma and tissues. Half-lives for unmodified peptides can be as short as minutes. Strategies to address this include:

•           D-amino acid incorporation: Replacing L-residues with D-residues resists proteolytic cleavage while maintaining activity.

•           Cyclization: Head-to-tail or side-chain cyclization reduces conformational flexibility and enhances resistance.

•           PEGylation: Polyethylene glycol chains shield peptides, reducing protease access and renal clearance.

•           Albumin-binding motifs: Extending circulation by reversible albumin binding, as seen in GLP-1 analogs for diabetes.

Pharmacokinetic (PK) studies confirm that PEGylated and lipidated peptide conjugates show half-lives extended 5–10 fold compared with unconjugated peptides. However, balancing stability with receptor affinity remains a design challenge: over-modification may reduce bioactivity.

IMMUNOGENICITY AND SAFETY CONCERNS [52,53]

Peptides are generally less immunogenic than proteins, but modifications (unnatural amino acids, nanoparticle conjugation) may trigger immune recognition.

•           Repeated dosing: Chronic administration of peptide–drug conjugates can lead to neutralizing antibodies, reducing therapeutic efficacy.

•           Hydrogels: Peptide-based hydrogels may elicit local inflammatory responses depending on sequence and degradation products.

Mitigation strategies include rational sequence design (avoiding T-cell epitopes), using immune-tolerant linkers, and applying immunomodulatory coatings.

   

FUTURE PERSPECTIVES

 a. Artificial Intelligence and Computational Design [54,20]

The last decade has seen dramatic advances in AI for peptide discovery.

•           Machine learning models predict protease resistance, solubility, and receptor binding.

•           AlphaFold2-like tools accelerate secondary structure prediction, supporting rational design of self-assembling peptides.

•           De novo sequence generation: Generative AI models propose optimized peptide libraries for high-throughput screening.

 b. Theranostic and Multifunctional Platforms

Future systems will integrate therapy + imaging + targeting into a single construct.

 C. Oral and Transmucosal Delivery [55,56,57,58]

Despite decades of effort, oral peptide delivery remains challenging due to enzymatic degradation and poor permeability.

•           Mucoadhesive peptide carriers: Increase residence time at intestinal epithelium

•           Permeation enhancers: CPP-like peptides co-formulated with drugs increase epithelial transport

•           Microbiome-assisted delivery: Leveraging gut bacteria to produce therapeutic peptides in situ

•           Device-assisted oral systems: Microneedle capsules delivering peptides directly into intestinal walls.

CONCLUSION

Peptide-based drug delivery systems (PBDDS) have grown from simple therapeutic molecules into powerful and versatile delivery platforms. Historically, peptides were limited by rapid degradation, short circulation times, and poor membrane permeability. However, advances in peptide chemistry and nanotechnology have transformed these weaknesses into remarkable opportunities. Today, peptides serve not only as therapeutics but also as carriers, targeting ligands, and self-assembling building blocks for complex drug delivery systems.

Peptide–drug conjugates (PDCs) improve drug stability, tumour penetration, and controlled release. Cell-penetrating peptides (CPPs) allow direct transport of large molecules such as proteins, nucleic acids, and nanoparticles into cells, offering a safer alternative to viral vectors. Self-assembling peptides can organize into nanofibers, micelles, or hydrogels that act as depots for localized and sustained drug delivery. Functionalization of lipid, polymeric, and inorganic nanoparticles with peptides has further enabled highly targeted and multifunctional systems that combine therapy with imaging and diagnostics.

The future of PBDDS lies in overcoming these barriers through innovation. Artificial intelligence (AI) is revolutionizing peptide design by predicting stability, receptor binding, and structure, allowing faster and more precise development. Non-invasive routes like oral and transmucosal delivery are also gaining attention, supported by advances in mucoadhesive carriers, permeation enhancers, and device-assisted systems. Furthermore, multifunctional theranostic platforms that combine treatment, targeting, and real-time monitoring will likely define the next generation of peptide therapeutics. With ongoing advances in chemistry, nanotechnology, and AI, PBDDS are poised to make precision, patient-friendly, and highly effective therapies a clinical reality.

REFERENCES:

1.    Sinha NJ, Langenstein MG, Pochan DJ, Kloxin CJ, Saven JG. Peptide design and self-assembly into targeted nanostructure and functional materials. Chemical Reviews. 2021 Oct 28;121(22):13915-35.

2.    Berillo D, Yeskendir A, Zharkinbekov Z, Raziyeva K, Saparov A. Peptide-based drug delivery systems. Medicina. 2021 Nov 5;57(11):1209.

3.    Wang D, Yin F, Li Z, Zhang Y, Shi C. Current progress and remaining challenges of peptide–drug conjugates (PDCs): next generation of antibody-drug conjugates (ADCs)?. Journal of Nanobiotechnology. 2025 Apr 22;23(1):305.

4.    Habibi N, Kamaly N, Memic A, Shafiee H. Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery. Nano today. 2016 Feb 1;11(1):41-60.

5.    Dhara M. Smart polymeric nanostructures for targeted delivery of therapeutics. Journal of Macromolecular Science, Part A. 2020 Nov 7;58(4):269-84.

6.    Banting FG, Best CH. The internal secretion of the pancreas. Indian Journal of Medical Research. 2007 Mar 1;125(3):L251.

7.    du Vigneaud V, et al. The synthesis of oxytocin. J Am Chem Soc. 1954;76(12),3115-3131.

8.    Merrifield RB. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. Journal of the American Chemical Society. 1963 Jul;85(14):2149-54.

9.    Abuchowski A, Van Es T, Palczuk NC, Davis FF. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. Journal of Biological Chemistry. 1977 Jun 10;252(11):3578-81.

10.  Ruoslahti E. RGD and other recognition sequences for integrins. Annual review of cell and developmental biology. 1996 Nov;12(1):697-715.

11.  Cell-penetrating Peptides, Richard, Jean Philippe et al, Journal of Biological Chemistry, Volume 278, Issue 1, 585 – 590.

12.  Zhang S. Fabrication of novel biomaterials through molecular self-assembly. Nature biotechnology. 2003 Oct 1;21(10):1171-8.

13.  Dubowchik GM, Walker MA. Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs. Pharmacology & therapeutics. 1999 Aug 1;83(2):67-123.

14.  Desale K, Kuche K, Jain S. Cell-penetrating peptides (CPPs): an overview of applications for improving the potential of nanotherapeutics. Biomaterials Science. 2021;9(4):1153-88.

15.  Zhao L, et al. Enzyme-sensitive linkers in peptide–drug conjugates. Bioconjug Chem. 2019;30:1413–1426

16.  Habibi N, Kamaly N, Memic A, Shafiee H. Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery. Nano today. 2016 Feb 1;11(1):41-60.

17.  Han EL, Tang S, Kim D, Murray AM, Swingle KL, Hamilton AG, Mrksich K, Padilla MS, Palanki R, Li JJ, Mitchell MJ. Peptide-Functionalized Lipid Nanoparticles for Targeted Systemic mRNA Delivery to the Brain. Nano Lett. 2025 Jan 15;25(2):800-810. doi: 10.1021/acs.nanolett.4c05186. Epub 2024 Dec 17. PMID: 39688915.

18.  Oriol A, Larocca A, Leleu X, Hajek R, Hassoun H, Rodríguez-Otero P, Paner A, Schjesvold FH, Gullbo J, Richardson PG. Melflufen for relapsed and refractory multiple myeloma. Expert Opin Investig Drugs. 2020 Oct;29(10):1069-1078. doi: 10.1080/13543784.2020.1808884. Epub 2020 Sep 29. PMID: 32924646.

19.  Mehrotra N, Kharbanda S, Singh H. Peptide-based combination nanoformulations for cancer therapy. Nanomedicine. 2020 Sep 1;15(22):2201-17.

20.  Zhai S, Liu T, Lin S, Li D, Liu H, Yao X, Hou T. Artificial intelligence in peptide-based drug design. Drug Discov Today. 2025 Feb;30(2):104300. doi: 10.1016/j.drudis.2025.104300. Epub 2025 Jan 20. PMID: 39842504.

21.  Kharbikar BN, Zhong JX, Cuylear DL, Perez CA, Desai TA. Theranostic biomaterials for tissue engineering. Curr Opin Biomed Eng. 2021 Sep;19:100299.

22.  Jadhav K, Abhang A, Kole EB, Gadade D, Dusane A, Iyer A, Sharma A, Rout SK, Gholap AD, Naik J, Verma RK, Rojekar S. Peptide-Drug Conjugates as Next-Generation Therapeutics: Exploring the Potential and Clinical Progress. Bioengineering (Basel). 2025 Apr 30;12(5):481.

23.  Alas M, Saghaeidehkordi A, Kaur K. Peptide–drug conjugates with different linkers for cancer therapy. Journal of medicinal chemistry. 2020 Dec 31;64(1):216-32.

24.  Cooper BM, Iegre J, O'Donovan DH, Halvarsson MÖ, Spring DR. Peptides as a platform for targeted therapeutics for cancer: peptide–drug conjugates (PDCs). Chemical society reviews. 2021;50(3):1480-94.

25.  Abed HF, Abuwatfa WH, Husseini GA. Redox-Responsive Drug Delivery Systems: A Chemical Perspective. Nanomaterials (Basel). 2022 Sep 14;12(18):3183. doi: 10.3390/nano12183183. PMID: 36144971; PMCID: PMC9503659.

26.  Yang Li, Yiming Zhou, Xiuli Yue, Zhifei Dai, Cyanine conjugates in cancer theranostics, Bioactive Materials, Volume 6, Issue 3, 2021, Pages 794-809, ISSN 2452-199X.

27.  Khan A, Tripathi A, Gandhi M, Bellare J, Srivastava R. Development of injectable upconversion nanoparticle‐conjugated doxorubicin theranostics electrospun nanostructure for targeted photochemotherapy in breast cancer. Journal of Biomedical Materials Research Part A. 2024 Sep;112(9):1612-26.

28.  Kang S, Lee S, Park S. iRGD peptide as a tumor-penetrating enhancer for tumor-targeted drug delivery. Polymers. 2020 Aug 24;12(9):1906.

29.  Petrie TA, Raynor JE, Dumbauld DW, Lee TT, Jagtap S, Templeman KL, Collard DM, García AJ. Multivalent integrin-specific ligands enhance tissue healing and biomaterial integration. Sci Transl Med. 2010 Aug 18;2(45):45ra60. doi: 10.1126/scitranslmed.3001002. PMID: 20720217; PMCID: PMC3128787.

30.  Conibear AC, Schmid A, Kamalov M, Becker CF, Bello C. Recent advances in peptide-based approaches for cancer treatment. Current Medicinal Chemistry. 2020 Mar 1;27(8):1174-205.

31.  Charron CL, Hickey JL, Nsiama TK, Cruickshank DR, Turnbull WL, Luyt LG. Molecular imaging probes derived from natural peptides. Natural product reports. 2016;33(6):761-800.

32.  Nugrahadi, P.P.; Hinrichs, W.L.J.; Frijlink, H.W.; Schöneich, C.; Avanti, C. Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review. Pharmaceutics 2023, 15, 935.

33.  Fujita Y, Taguchi H. Nanoparticle-Based Peptide Vaccines. Micro and Nanotechnology in Vaccine Development. 2017:149–70. doi: 10.1016/B978-0-323-39981-4.00008-7. Epub 2016 Oct 7. PMCID: PMC7152328.

34.  Mueller LK, Baumruck AC, Zhdanova H, Tietze AA. Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides. Front Bioeng Biotechnol. 2020 Mar 4;8:162. doi: 10.3389/fbioe.2020.00162. PMID: 32195241; PMCID: PMC7064641.

35.  Scodeller, P.; Asciutto, E.K. Targeting Tumors Using Peptides. Molecules 2020, 25, 808.

36.  Derakhshankhah H, Jafari S. Cell penetrating peptides: A concise review with emphasis on biomedical applications. Biomedicine & Pharmacotherapy. 2018 Dec 1;108:1090-6.

37.  Datta N, et al. Cyclization and D-amino acid substitution for CPP stability. Chem Biol Drug Des. 2025;105(2):321–333.

38.  Li Z, Zhu Y, Matson JB. pH-responsive self-assembling peptide-based biomaterials: designs and applications. ACS applied bio materials. 2022 May 3;5(10):4635-51.

39.  Yang J, An HW, Wang H. Self-assembled peptide drug delivery systems. ACS Applied Bio Materials. 2020 Jul 10;4(1):24-46.

40.  Han EL, Tang S, Kim D, Murray AM, Swingle KL, Hamilton AG, Mrksich K, Padilla MS, Palanki R, Li JJ, Mitchell MJ. Peptide-functionalized lipid nanoparticles for targeted systemic mRNA delivery to the brain. Nano Letters. 2024 Dec 17;25(2):800-10.

41.  Ma W, Chen M, Kaushal S, McElroy M, Zhang Y, Ozkan C, Bouvet M, Kruse C, Grotjahn D, Ichim T, Minev B. PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses. International journal of nanomedicine. 2012 Mar 15:1475-87.

42.  Osada K, Kataoka K. Drug and gene delivery based on supramolecular assembly of PEG-polypeptide hybrid block copolymers. Peptide hybrid polymers. 2006 Mar 16:113-53.

43.  Vardaxi A, Kafetzi M, Pispas S. Polymeric Nanostructures Containing Proteins and Peptides for Pharmaceutical Applications. Polymers (Basel). 2022 Feb 16;14(4):777. doi: 10.3390/polym14040777. PMID: 35215689; PMCID: PMC8877994.

44.  Malmsten M. Inorganic nanomaterials as delivery systems for proteins, peptides, DNA, and siRNA. Current Opinion in Colloid & Interface Science. 2013 Oct 1;18(5):468-80.

45.  Wang R, Wang Z, Guo Y, Li H, Chen Z. Design of a RADA16-based self-assembling peptide nanofiber scaffold for biomedical applications. Journal of Biomaterials Science, Polymer Edition. 2019 Jun 13;30(9):713-36.

46.  Jin J, Sun C, Xu K, Sun X, Cao L, Liu L. Multifunctional self-healing peptide hydrogel for wound healing. International Journal of Biological Macromolecules. 2024 Mar 1; 261:129734.

47.  Wang H, Luo Z, Wang Y, He T, Yang C, Ren C, Ma L, Gong C, Li X, Yang Z. Enzyme‐catalyzed formation of supramolecular hydrogels as promising vaccine adjuvants. Advanced Functional Materials. 2016 Mar;26(11):1822-9.

48.  Thang NH, Van Phuc N, Nhi TT, Cuong DX, Minh DQ. Novel polymer-based hydrogels of recent research in drug delivery for disease treatment related to SARS-CoV-2 virus. Express Polymer Letters. 2024 Feb 1;18(2).

49.  Raza F, Zhu Y, Chen L, You X, Zhang J, Khan A, Khan MW, Hasnat M, Zafar H, Wu J, Ge L. Paclitaxel-loaded pH responsive hydrogel based on self-assembled peptides for tumor targeting. Biomaterials science. 2019;7(5):2023-36.

50.  Adessi C, Soto C. Strategies to improve stability and bioavailability of peptide drugs. Frontiers in Medicinal Chemistry-Online. 2004 Jan 1;1(1):513-28.

51.  Lamers C. Overcoming the shortcomings of peptide-based therapeutics. Future Drug Discovery. 2022 Jun 1;4(2):FDD75.

52.  Achilleos K, Petrou C, Nicolaidou V, Sarigiannis Y. Beyond Efficacy: Ensuring Safety in Peptide Therapeutics through Immunogenicity Assessment. Journal of Peptide Science. 2025 Jun;31(6):e70016.

53.  Real-Fernandez F, Errante F, Di Santo A, Papini AM, Rovero P. Therapeutic proteins immunogenicity: a peptide point of view. Exploration of Drug Science. 2023; 1:377-87.

54.  Zhai S, Liu T, Lin S, Li D, Liu H, Yao X, Hou T. Artificial intelligence in peptide-based drug design. Drug Discovery Today. 2025 Jan 20:104300.

55.  Parida P, Prusty AK, Prusty RK, Jena BR, Panda D, Das S. Overcoming hurdles in oral protein and peptide drug delivery: Strategies for future prospective. InAdvancement in Animal Handling and Generative AI for Pre-clinical Studies 2025 Aug 25 (pp. 28-41). CRC Press.

56.  Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Advanced drug delivery reviews. 2001 Mar 23;47(1):39-54.

57.  Nicze M, Borówka M, Dec A, Niemiec A, Bułdak Ł, Okopień B. The current and promising oral delivery methods for protein-and peptide-based drugs. International Journal of Molecular Sciences. 2024 Jan 9;25(2):815.

58.  Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. 

59.  Nature reviews Drug discovery. 2014 Sep;13(9):655-72.