Aug 2026· Journal of Pharmaceutical Innovation· Vol 22· 0 citations· 218 references
TL;DR
This review presents a unified innovation framework that integrates upstream molecular engineering strategies including cyclization, peptide stapling, D- and β-amino acid substitution, PEGylation, and backbone modification with downstream advanced delivery platforms such as nanocarriers, microneedles, self-assembling hydrogels, and stimuli-responsive systems, while also addressing critical translational considerations including scalability, regulatory requirements, and manufacturing consistency.
Abstract
Peptide-based therapeutics have become a flexible type of medicine that combines high target specificity and strong biological activity with good safety profiles. They effectively connect small-molecule drugs and biologics. Since insulin was first used in 1922, more than 100 peptide drugs have been approved around the world, and their use is growing in diabetes, cancer, rare diseases, and autoimmune disorders. However, their clinical use is still limited by rapid enzymatic degradation, short half-life, poor membrane permeability, low oral bioavailability, and formulation instability. This review presents a unified innovation framework that integrates upstream molecular engineering strategies including cyclization, peptide stapling, D- and β-amino acid substitution, PEGylation, and backbone modification with downstream advanced delivery platforms such as nanocarriers, microneedles, self-assembling hydrogels, and stimuli-responsive systems, while also addressing critical translational considerations including scalability, regulatory requirements, and manufacturing consistency. By critically linking structural modifications at the molecular level with formulation performance and clinical translation factors, and by evaluating both approved products and persistent gaps in predictive modelling and patient-centric delivery, this work offers practical insights that go beyond the scope of most existing reviews. The integrated perspective presented here highlights how these combined approaches are shifting peptide therapeutics from conventional injectable formats toward more stable, convenient, and precisely targeted solutions, paving the way for the next generation of patient-friendly peptide medicines.
Nanoparticle-based drug delivery systems have become an important component of modern nanomedicine, enabling improved drug protection, controlled release, targeted delivery, and the modulation of pharmacokinetic behavior. Their therapeutic performance is governed by physicochemical properties such as size, shape, surface chemistry, and material composition, which influence biological interactions, biodistribution, cellular uptake, and clearance. This review examines major nanoparticle platforms, including polymeric, lipid-based, inorganic, carbon-based, and hybrid systems, together with passive and active targeting and endogenous and externally triggered release strategies. Current and emerging applications in oncology, infectious diseases, central nervous system disorders, gene therapy, and vaccines are discussed alongside theranostic and combination-delivery approaches. Particular emphasis is placed on computational modeling, artificial intelligence, and digital twins for formulation optimization and personalized nanomedicine. Key barriers to clinical translation, including manufacturing scalability, biological variability, limitations of EPR-mediated targeting, regulatory standardization, and long-term safety, are critically evaluated. Finally, emerging directions in sustainable nanomanufacturing and biomimetic delivery are discussed. By integrating biological mechanisms with computational, manufacturing, regulatory, and clinical considerations, this review provides a translational perspective on advancing nanoparticle drug-delivery systems from laboratory development toward clinical implementation.
Subin Antony Jose, Benjamin Crutchfield, M. Caballero et al.· Molecules· 0 citations
This review comprehensively examines major nanocarrier platforms, including lipid-based, polymeric, inorganic, and hybrid systems, with emphasis on their structural design and functional properties.
Nithya Ajay, Anu Shibi Anilkumar, R. Veerabathiran· Therapeutic delivery· 0 citations
G-protein Coupled Receptors (GPCRs) are the largest family of classical membrane receptors and the most important class of pharmacological targets, playing roles in many physiological and pathological processes. Targeting a GPCR is a challenging approach because traditional drugs and similar therapeutics have a number of significant drawbacks, including low aqueous solubility, low bioavailability, rapid metabolic degradation, low tissue specificity, and off-target effects. This review discusses different nanocarrier-based drug delivery strategies to improve the therapeutic efficacy, targeting efficiency, and translational potential of drugs acting on GPCRs.
A systematic review of peer-reviewed published articles to explore the latest developments in GPCR biology, GPCR signalling pathways, and drug delivery using nanocarriers was conducted. Major nanoplatforms, such as liposomes, polymeric nanoparticles, dendrimers, and hybrid nanosystems, were studied based on their design principles, targeting strategies, and therapeutic applications. Preclinical, mechanistic, and early translational studies that were relevant were included.
Nanocarrier-based systems have multiple advantages in GPCR-targeted therapy, such as enhanced drug stability, increased bioavailability, controlled release, and reduced systemic toxicity. Functionalization of nanocarriers may improve delivery in a receptor-specific manner and facilitate transport across biological barriers, such as the blood-brain barrier. These systems also support multiple functions, including co-delivery of therapeutics, nucleic acids, and diagnostic components. Promising applications have been identified in oncology, neurological disorders, cardiovascular diseases, and inflammatory conditions. However, there are still challenges in translation, particularly with regard to immunogenicity, long-term safety, manufacturing scalability, and regulatory approval.
The combined use of GPCR pharmacology with state-of-the-art nanocarrier engineering is a promising approach to improve receptor selectivity and therapeutic precision. Novel instruments, such as artificial intelligence, molecular modelling, and systems pharmacology, may further aid the optimisation of ligand selection, carrier design, and personalised therapeutic development.
Nanocarrier-mediated drug delivery is a sensible and highly promising strategy to address the limitations of conventional GPCR therapeutics. In addition, developments in targeted nanomedicine may accelerate the development of accurate and individualised GPCR-targeted therapeutic treatments.
Pranay Wal, Jyotsana Dwivedi, K. Khairunnisa et al.· Current Drug Targets· 0 citations
Peptide-based therapeutics are gaining popularity as next-generation drugs because of their potent bioactivity, high specificity, and broad applications in immunomodulatory, antiviral, anticancer, and antimicrobial therapy. Membrane-active peptides (MAPs) are particularly promising, yet poor solubility, stability, pharmacokinetics, manufacturing complexity, and limited delivery options have restricted their clinical translation. This review focuses on computational approaches developed to address these challenges at the peptide-design stage and bridge the gap between preclinical promise and clinical utility. The goal here is to provide a broad overview of tools for in silico MAP design, prediction of functional structural ensembles and physicochemical properties, structure–function relationships, drug-target interactions, and formulation strategies for in vivo delivery. These approaches span bioinformatics, molecular dynamics and molecular modeling, and emerging artificial intelligence and machine learning platforms, including hybrid computational-experimental strategies, chemical modification and conjugation, and nanotechnology-based delivery systems. These tools are improving key peptide–drug properties, including plasma stability, target specificity, efficacy, and delivery. Continued advances in computational design may enable MAPs to address challenging diseases, engage traditionally undruggable targets, and translate their substantial therapeutic potential into clinically effective treatments.
A structured translational roadmap is proposed that prioritizes biologically predictive design, fit-for-purpose safety assessment, scalable good manufacturing practice production, early regulatory alignment, and clinically meaningful benefit over unnecessary structural complexity.
Yi Li, Rui Luo, Yuxuan Li et al.· Biomedicine & pharmacotherap...· 0 citations
Peptide therapeutics occupy a unique position between small organic compounds and large protein biomolecules, combining high specificity, strong pharmacological efficacy, and favourable safety profiles. Consequently, they have emerged as important therapeutic agents for a wide range of diseases, including metabolic and oncological disorders. However, oral administration of peptide drugs remains a major challenge due to extensive enzymatic degradation, low intestinal permeability, mucus entrapment, and presystemic metabolism within the gastrointestinal tract. This review provides a comprehensive overview of contemporary strategies for improving oral peptide delivery, with special emphasis on emerging pharmaceutical formulation technologies, bioinspired delivery systems and ingestible device-assisted approaches. A qualitative literature search was conducted using major scientific databases and included relevant publications available up to May 2026. The analysis identified the main barriers responsible for low oral bioavailability of peptide drugs, as well as promising approaches to overcoming these obstacles, including peptide modification, enzyme inhibition, permeation enhancement, mucolytic strategies, and advanced carrier systems. Special attention is given to multifunctional carrier systems, ingestible medical devices and bile acid-inspired technologies as emerging directions in oral peptide delivery. The convergence of pharmaceutical sciences, bioinspired formulation strategies and biomedical engineering is expected to accelerate the clinical translation of oral peptide formulations and enable their therapeutic potential to be fully exploited.
Sara Vasović, Lucija Vasović, Nikola Martić et al.· Pharmaceuticals· 0 citations
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