Therapeutic Peptides and Protein Drugs: Current Landscape and Future Perspectives in Delivery Strategies

Today, we are sharing an important review article published in the Journal of Controlled Releasein 2026. This article systematically outlines the challenges faced in the delivery of therapeutic peptides and protein drugs, established and emerging solutions, and provides an in-depth analysis of how these strategies collectively shape modern successful therapies. The article points out that peptide and protein drugs, with their advantages of high target specificity, well-defined mechanisms of action, and low toxicity, have become the fastest-growing segment of the global pharmaceutical industry. However, their inherent drawbacks—such as susceptibility to proteolytic degradation, poor cell membrane permeability, and short in vivo circulation half-lives—have long limited the expansion of their clinical applications. In recent years, with the deep integration of structural biology, materials science, and artificial intelligence technologies, innovations in delivery technologies are reshaping the R&D paradigm for peptide and protein drugs. This is driving a shift in treatment modalities from traditional injectable administration to non-invasive delivery and from systemic exposure to precise targeted delivery.

1. Molecular Engineering: Enhancing Drug-like Properties from the Source

Molecular engineering, involving the directed modification of the primary structure and spatial conformation of peptides and proteins, can fundamentally address their issues of poor stability, suboptimal pharmacokinetics, and insufficient targeting. It is a core technological approach in the current R&D of peptide and protein drugs.

1.1 Strategies for Metabolic Stability Optimization

Different structural modification strategies enhance a drug's resistance to proteolytic degradation through distinct mechanisms, with significant differences in their impact on biological activity and clinical maturity.

• Backbone Modification:​ One of the most widely applied techniques. Introducing D-amino acids, N-methylated amino acids, or unnatural amino acids disrupts protease recognition motifs and increases molecular conformational rigidity. This significantly extends the in vivo half-life while preserving biological activity. Several drugs employing this technology have been approved for marketing.

• Terminal Modification:​ Acetylation of the N-terminus or amidation of the C-terminus of the peptide chain blocks the action of exopeptidases. This method is simple and has minimal impact on molecular structure but does not provide protection against endopeptidases.

• Cyclization Technology:​ By eliminating the free termini of the peptide chain and pre-organizing the molecule into its bioactive conformation, cyclization simultaneously enhances stability and receptor affinity. It is one of the fastest-developing modification strategies in recent years. The all-hydrocarbon stapled peptide technology, which introduces covalent crosslinks into α-helical structures, significantly improves peptide cell-penetrating ability and metabolic stability. Several candidates using this approach are in clinical stages.

• Peptoids:​ The side chain is transferred from the α-carbon to the amide nitrogen, fundamentally altering the molecular backbone. Peptoids possess the strongest resistance to proteolytic degradation but also introduce challenges of unpredictable conformation and difficulty in retaining biological activity, and are currently mainly in the preclinical research stage.

1.2 Pharmacokinetic Optimization Technologies

Extending the in vivo circulation half-life is a critical need for the clinical application of peptide and protein drugs, and several mature technological routes have been established.

• PEGylation:​ Coupling hydrophilic polyethylene glycol (PEG) chains to the drug molecule increases its hydrodynamic radius, reducing glomerular filtration. It also shields protease recognition sites and lowers immunogenicity. It was the first half-life extension technology to achieve clinical application. However, recent concerns about anti-PEG antibodies causing accelerated blood clearance and the long-term accumulation of non-biodegradable PEG have driven the development of alternative polymers like poly(2-oxazoline) and polysarcosine.

• Lipidation:​ Coupling fatty acid chains to peptide molecules promotes their reversible binding to serum albumin, significantly extending circulation time. This technology has achieved great success in incretin-based drugs. Blockbuster drugs like liraglutide, semaglutide, and tirzepatide all employ lipidation, enabling once-weekly or even longer dosing intervals.

• Glycosylation:​ Improves protein folding stability and pharmacokinetic properties.

• Fc Fusion and Albumin Fusion Technologies:​ Leverage the neonatal Fc receptor (FcRn) recycling mechanism to extend drug half-life to days or even weeks. These are widely used in the development of antibody fusion proteins and long-acting clotting factors.

• Peptide-Drug Conjugates (PDCs):​ An emerging treatment modality that links targeting peptides to cytotoxic drugs via cleavable linkers. This enables tumor-specific activation of the drug, significantly improving therapeutic potency while reducing systemic toxicity. Several PDC drugs have been approved for treating neuroendocrine tumors and multiple myeloma. Their modular design concept provides a new思路 for developing next-generation precision therapeutics.

1.3 Enhancing Targeting and Potency

The combination of directed evolution and rational design is the current mainstream paradigm for improving drug targeting and potency.

• Directed Evolution:​ Constructs large-scale mutation libraries and performs multiple rounds of screening to discover beneficial mutations difficult to predict by rational design. It has achieved widespread success in areas like antibody affinity maturation and enzyme stability optimization. The first fully human antibody, adalimumab, was discovered via phage display technology.

• Rational Design:​ Based on high-resolution structural biology data, it performs site-directed mutagenesis on key residues of the drug molecule, allowing for more efficient optimization of its binding properties and function. The emergence of AI structure prediction tools like AlphaFold2 has greatly accelerated the rational design process, significantly reducing experimental screening workload.

• Cell-Penetrating Peptides (CPPs):​ Can transport large molecular cargoes across the cell membrane into the cytoplasm, enabling drug development for intracellular targets. However, challenges remain regarding insufficient specificity and low endosomal escape efficiency.

• Antibody-Drug Conjugates (ADCs):​ Combine the high specificity of antibodies with the potent killing effect of cytotoxic drugs, making them a current research hotspot in cancer therapy. The development of new-generation site-specific conjugation technologies addresses the issue of drug-to-antibody ratio heterogeneity caused by traditional conjugation methods, significantly improving the therapeutic index and batch consistency of ADCs.

2. Drug Carrier Systems: Delivery Platforms to Overcome Biological Barriers

Although molecular engineering has significantly improved the drug-like properties of peptides and proteins, many therapeutic candidates still require drug carrier systems to overcome biological barriers and achieve effective tissue distribution and intracellular delivery. Carrier systems must protect the structural integrity of the drug in vivo, control its release kinetics, and target specific tissues or cells.

2.1 Common Challenges for Carrier Systems

Compared to small molecules and nucleic acid drugs, carrier development for peptides and proteins faces unique challenges. Protein molecules have complex tertiary and quaternary structures, are highly sensitive to interfacial stress, pH changes, organic solvents, and dehydration processes, and are prone to denaturation and aggregation during carrier preparation. Furthermore, the heterogeneous surface charge distribution and large hydrodynamic size of protein molecules generally lead to low encapsulation efficiency and a tendency for burst release. After in vivo administration, the rapid formation of a protein corona on the nanoparticle surface alters its original physicochemical properties and in vivo behavior. This is a major reason for the failure of many promising preclinical carrier systems in clinical trials.

2.2 Translational Progress of Mainstream Carrier Systems

• Micelles:​ One of the earliest carrier systems used for peptide drug delivery. Their hydrophobic core can effectively solubilize hydrophobic cyclic peptides. The cyclosporine A ocular nano-micelle formulation Cequa® has received FDA approval. However, micelles have a critical micelle concentration (CMC) issue, where they can dissociate upon in vivo dilution, leading to premature drug release, limiting their application in systemic administration.

• Liposomes:​ Offer good biocompatibility and structural tunability, capable of co-encapsulating hydrophilic and hydrophobic drugs. Mepact® (mifamurtide liposomes) is approved in Europe for osteosarcoma treatment. However, issues of drug leakage and the accelerated blood clearance phenomenon associated with PEGylation remain to be solved.

• Hydrogels:​ Three-dimensional cross-linked polymer networks that provide protein drugs with a protective, physiological-like environment, enabling long-term local sustained release. They are widely used in areas like diabetic ulcers, surgical hemostasis, and joint treatment. Main limitations include initial burst release, heterogeneous in vivo degradation, and potential foreign body reactions after implantation.

• Lipid Nanoparticles (LNPs):​ The tremendous success of LNPs in mRNA vaccines has laid the foundation for their application in protein drug delivery. However, unlike nucleic acids, protein molecules lack strong electrostatic interactions with ionizable lipids, leading to generally low encapsulation efficiency. Furthermore, insufficient endosomal escape efficiency remains a major bottleneck hindering their clinical translation.

• Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs):​ Exhibit good biocompatibility and controlled release properties, showing great potential in oral insulin delivery. However, issues like lipid polymorphic transitions and drug leakage during storage require further resolution.

• Polymeric Nanoparticles:​ Particularly poly(lactic-co-glycolic acid) (PLGA) nanoparticles, offer good biodegradability and tunable release kinetics. However, the water-oil interface during double emulsion preparation can cause protein denaturation, and the acidic microenvironment produced by PLGA degradation can further accelerate protein inactivation.

3. Administration Routes: From Injection Dominance to Multiple Parallel Pathways

Parenteral administration has long been the primary route for peptide and protein drugs. However, patient compliance issues and the medical burden associated with injections have driven the rapid development of non-invasive delivery technologies. In recent years, significant breakthroughs have been made in oral, transdermal, intranasal, and pulmonary administration routes, providing more options for the clinical application of peptide and protein drugs.

3.1 Innovations in Parenteral Administration

• Intravenous (IV) Administration:​ Provides complete bioavailability and immediate systemic exposure. It is the preferred route for acute treatment and tumor antibody drugs but requires professional medical personnel and has poor patient compliance. Recently, the development of high-concentration subcutaneous (SC) formulations has led to the shift of many IV drugs to SC administration. The application of recombinant human hyaluronidase (rHuPH20) can degrade hyaluronic acid in the extracellular matrix, allowing the injection of larger drug volumes, significantly improving the patient treatment experience. Subcutaneous formulations of several monoclonal antibodies, such as trastuzumab and daratumumab, have received FDA approval, enabling administration within minutes.

• Intramuscular (IM) Injection:​ Primarily used for vaccines and long-acting formulations. The RSV prophylactic drug nirsevimab, approved in 2022, uses Fc engineering to extend its half-life, requiring only a single annual IM injection to provide full-season protection for infants.

• Intrathecal (IT) and Intravitreal (IVT) Injections:​ For immunologically privileged sites like the central nervous system and the eye, these routes are necessary to achieve effective drug concentrations. IT ziconotide for severe pain and various anti-VEGF antibody IVT injections for wet age-related macular degeneration have achieved good clinical outcomes.

3.2 Breakthroughs in Non-Parenteral Administration

• Oral Administration:​ The most ideal route, but it faces multiple barriers including gastric acid degradation, intestinal protease hydrolysis, the mucus barrier, and epithelial tight junctions, resulting in oral bioavailability of less than 1% for most peptides and proteins. Recent milestone breakthroughs include oral semaglutide, which employs the absorption enhancer SNAC to locally increase gastric pH, protect the drug from gastric acid, and promote its absorption in gastric epithelial cells, becoming the first approved oral GLP-1 receptor agonist. Furthermore, oral robotic capsules based on mechanical delivery principles can automatically inject the drug into the intestinal wall, bypassing the epithelial barrier, achieving bioavailability comparable to subcutaneous injection in preclinical studies.

• Transdermal Administration:​ Offers advantages like avoiding first-pass metabolism, convenience, and the ability to terminate dosing. However, the stratum corneum barrier limits the permeation of large molecules. Microneedle technology creates micron-sized channels in the skin, effectively overcoming the stratum corneum barrier for transdermal delivery of peptides and proteins. Several insulin microneedle patches are in clinical research.

• Intranasal Administration:​ Offers rapid absorption and the potential for brain delivery by bypassing the blood-brain barrier. Nasal glucagon is approved for emergency treatment of severe hypoglycemia, and intranasal carbetocin for Prader-Willi syndrome has entered Phase 3 trials.

• Pulmonary Administration:​ Leverages the lungs' large surface area and thin alveolar epithelium for rapid systemic absorption of peptides and proteins. Inhaled insulin Afrezza® is FDA-approved, with an onset of action even faster than subcutaneous rapid-acting insulin. Other mucosal routes like sublingual/buccal, ocular, and vaginal administration also show good application prospects for specific indications.

4. Current Status and Future Challenges

4.1. Development Landscape

Currently, the field of peptide and protein drug delivery has entered a mature stage of platform-based development. Considerations for delivery technologies are now being integrated earlier, from the late stages to the early discovery phases of drug R&D. The tremendous commercial success of monoclonal antibodies and incretin-based drugs validates the clinical value and market potential of delivery technology innovation. Artificial intelligence is permeating the entire drug R&D pipeline, from molecular design and carrier screening to formulation optimization, significantly improving efficiency. However, the field still faces numerous unresolved scientific questions and translational challenges that limit the development of next-generation peptide and protein drugs.

4.2 Core Challenges for the Next Decade

• Intracellular Delivery:​ The most fundamental scientific challenge. Although nanocarriers can deliver drugs into cells, the vast majority are trapped in endosomes and ultimately degraded, with less than 10% escaping to the cytosol to exert their effect. Improving endosomal escape efficiency is key to developing drugs for intracellular targets.

• Bioavailability and Inter-individual Variability in Non-Parenteral Routes:​ Approved oral peptide drugs are all highly potent, low-dose molecules. Achieving efficient oral delivery for large protein drugs remains a significant challenge.

• Cooperative Design of Molecular Engineering and Delivery Systems:​ Future development requires considering the requirements of the delivery system at the early stages of drug design to achieve synergistic optimization of molecular structure and carrier properties, moving beyond the traditional sequential optimization model.

• Other Challenges:​ Scaling up the production and quality control of nanocarriers, insufficient predictive power of preclinical animal models, and other issues also hinder the clinical translation of delivery technologies.

4.3 Future Outlook

In the future, the development of peptide and protein drug delivery technologies will place greater emphasis on integrated engineering design. Through the synergistic innovation of molecular engineering, carrier design, and administration technologies, the therapeutic efficacy and patient compliance of drugs will be comprehensively enhanced. Artificial intelligence will play an increasingly important role in multi-parameter optimization and predictive design, accelerating the translation from lab to clinic. With continuous breakthroughs in delivery technologies, peptide and protein drugs are expected to cover more currently "undruggable" targets, bringing new hope for treating major diseases like cancer, neurodegenerative diseases, and rare disorders.

Original Article：Jin, Qiongli, et al. "Unfolding of RNA secondary structure impairs RNA stability to fine-tune phosphate starvation responses in rice roots." Plant Communications 7.4 (2026).