Explore studies of peptide delivery.
Chimeric peptides coupling opioid peptides to BBB transport vectors allow brain delivery of enkephalin and dynorphin analogs in vivo. The strategy has advantages for addiction drug development.
Pardridge, W M · Review
Cyclotides combine exceptional structural stability (thermal, enzymatic, chemical resistance) with sequence-tolerant scaffolding capability, enabling design of stable peptide drugs through grafting bioactive sequences into the cyclotide framework.
Craik, David J; Simonsen, Shane; Daly, Norelle L · Review
A novel Na+/Cl--coupled opioid peptide transport system was identified in retinal pigment epithelial cells, enabling active regulation of local opioid peptide concentrations at the blood-retinal barrier.
Hu, Huankai; Miyauchi, Seiji; Bridges, Christy C; Smith, Sylvia B; Ganapathy, Vadivel · In Vitro
GHK peptide incorporated into a biotinylated collagenous wound dressing accelerated rat dermal wound healing: faster wound closure, enhanced granulation tissue formation, improved collagen deposition, and better overall histological healing scores versus scaffold alone.
Arul, V; Gopinath, D; Gomathi, K; Jayakumar, R · Animal Study
Glycosylation of opioid and other neuropeptides enhanced BBB penetration, metabolic stability, and analgesic potency after peripheral administration, establishing glycopeptides as a practical strategy for delivering peptide drugs to the brain.
Polt, Robin; Dhanasekaran, Muthu; Keyari, Charles M · Review
Macrocyclic C5a antagonists achieved pharmacologically active transdermal penetration in rats, with measurable anti-inflammatory effects from topical application — establishing the feasibility of transdermal delivery for cyclic peptide anti-inflammatory drugs.
Proctor, Lavinia M; Woodruff, Trent M; Sharma, Prakirti; Shiels, Ian A; Taylor, Stephen M · Animal Study
MCoTI-II was internalized into human cells through macropinocytosis (not receptor-mediated endocytosis), accumulating in cytoplasm — demonstrating that macrocyclic peptide scaffolds can access intracellular targets, dramatically expanding their drug design utility.
Greenwood, Kathryn P; Daly, Norelle L; Brown, Darren L; Stow, Jennifer L; Craik, David J · In Vitro
Fmoc-diphenylalanine self-assembled into nanofibrillar hydrogels supporting 3D cell culture with maintained viability and function, demonstrating that extremely simple dipeptides can create functional tissue engineering scaffolds through molecular self-organization.
Liebmann, Thomas; Rydholm, Susanna; Akpe, Victor; Brismar, Hjalmar · In Vitro
MAX1 beta-hairpin peptide hydrogel demonstrated inherent broad-spectrum antibacterial activity against gram-positive and gram-negative bacteria through its cationic amphipathic surface structure — a self-sterilizing wound dressing biomaterial requiring no added antibiotic agents.
Salick, Daphne A; Kretsinger, Juliana K; Pochan, Darrin J; Schneider, Joel P · In Vitro
Self-assembling peptide hydrogels incorporating matrix metalloproteinase (MMP)-sensitive substrate sequences degraded in response to cell-secreted MMPs during tissue repair, creating enzyme-responsive smart scaffolds that adapt to the wound healing environment.
Chau, Ying; Luo, Ying; Cheung, Alex C Y; Nagai, Yusuke; Zhang, Shuguang; Kobler, James B; Zeitels, Steven M; Langer, Robert · In Vitro
Peptide amphiphile nanofibers self-assembled into scaffolds supporting dental stem cell (DPSC) adhesion, proliferation, and odontogenic differentiation — validating self-assembling peptide biomaterials for injectable dental tissue regeneration applications.
Galler, Kerstin M; Cavender, Adriana; Yuwono, Virany; Dong, He; Shi, Songtao; Schmalz, Gottfried; Hartgerink, Jeffrey D; D'Souza, Rena N · In Vitro
KPV peptide cannot cross the skin by passive diffusion — levels were undetectable. But combining two enhancement technologies dramatically changed this: microneedles alone increased permeation to 4.4 μg/cm²/h, iontophoresis (electrical current) alone was 8-fold better than microneedles, and combining both technologies boosted delivery 35-fold over microneedles alone. Skin retention also improved dramatically — 10-fold higher KPV was retained in the skin when using iontophoresis or the combination approach. Confocal imaging confirmed the peptide penetrated beyond 100 μm depth, reaching the lower epidermis.
Pawar, Kasturi; Kolli, Chandra S; Rangari, Vijaya K; Babu, R Jayachandra · In Vitro Laboratory Study
Cell penetrating peptides (CPPs) are short peptide sequences that can cross cell membranes — a feat that most therapeutic molecules cannot accomplish. This review classifies CPPs into categories based on their origin and properties, describes their uptake mechanisms (direct penetration vs. endocytosis), and catalogs their biomedical applications as delivery vehicles for nucleic acids, proteins, siRNA, drugs, and nanoparticles. The key insight is that CPPs can carry virtually any type of therapeutic cargo across cell membranes, making them one of the most versatile drug delivery tools in biomedical research.
Derakhshankhah, Hossein; Jafari, Samira · Review
The cell-penetrating peptide (CPP) was the key ingredient. Without CPP, the PLGA nanoparticles carrying plasmid DNA showed minimal cell uptake. With CPP attached, 84% of Beas-2B cells and 97% of A549 lung cancer cells internalized the nanoparticles within just 3 hours. The particles entered cells mainly through clathrin-mediated endocytosis, a common cellular intake pathway. Once inside, the particles appeared to escape the endosome compartment, which is critical for the DNA cargo to reach its target. The delivered DNA produced green fluorescent protein (eGFP) in Beas-2B cells after 96 hours, confirming functional gene delivery. The nanoparticles released about 50% of their DNA cargo in the first 24 hours, with encapsulation efficiency high enough to be practical.
Gomes Dos Reis, Larissa; Lee, Wing-Hin; Svolos, Maree; Moir, Lyn M; Jaber, Rima; Engel, Andrea; Windhab, Norbert; Young, Paul M; Traini, Daniela · In Vitro (Cell Culture)
The core problem: cell-penetrating peptides (CPPs) have positive charges that can interfere with the function of attached cargo peptides inside cells. Direct conjugation often does not work reliably. The solution: an 8-unit PNA sequence conjugated to octa-arginine CPP (PNA1-CPP) paired with a complementary PNA attached to an autophagy-inducing peptide (PNA2-AIP). The two PNA strands hybridized, forming a stable 1:1 complex that kept the functional peptide connected to the CPP during delivery. Once inside cells, at least some of the PNA1-CPP/PNA2-AIP complexes dissociated, releasing the functional AIP from the positively charged CPP. The released PNA2-AIP induced significantly more autophagy than AIP directly conjugated to CPP (CPP-AIP). The PNA hybrid system also caused minimal cell death.
Hakata, Yoshiyuki; Ishikawa, Suzuka; Ohtsuki, Takashi; Miyazawa, Masaaki; Kitamatsu, Mizuki · In Vitro (Proof Of Concept)
The researchers created peptide dendrimer variants carrying fluorescent labels in their core. These labeled versions maintained the same siRNA transfection efficiency, pH-dependent aggregation, siRNA binding, and secondary structures as unlabeled dendrimers. FRET (fluorescence resonance energy transfer) experiments revealed the delivery mechanism in detail: at pH 7.4 (normal cellular pH), dendrimers and siRNA are tightly packed together in nanoparticles. At pH 5.0 (endosomal pH), the complex loosens and dendrimers are released into solution. At this acidic pH, the dendrimers destabilize endosomal membranes, enabling escape into the cytoplasm where siRNA can silence target genes. Colocalization studies showed dendrimers and siRNA stay together throughout the uptake process, separating only after reaching acidic endosomes. This pH-triggered release mechanism is what makes the system effective.
Heitz, Marc; Zamolo, Susanna; Javor, Sacha; Reymond, Jean-Louis · In Vitro (Mechanistic)
Exenatide is a peptide drug given by injection because it is destroyed in the gut and cannot cross the intestinal wall. Hydrophobic ion pairing (HIP) makes peptides lipophilic by pairing them with surfactant counterions. Two surfactant types were tested: cationic THA (tetraheptylammonium bromide) and anionic DOC (sodium docusate). Both formed stable complexes with exenatide. Exenatide-THA was more lipophilic (log D of 2.29 in simulated intestinal fluid vs 1.2 for exenatide-DOC). When loaded into lipid nanocarriers (41% Capmul MCM, 15% Captex 355, 40% Cremophor RH, 4% propylene glycol), the THA formulation showed: - 10-fold enhancement in intestinal apparent membrane permeability vs free exenatide - 28.0% ± 5.2% relative oral bioavailability in healthy rats The DOC formulation achieved 3-fold permeability enhancement and 16.3% ± 6.6% bioavailability. Neither formulation caused significant hemolytic activity at 0.25% concentration, indicating safety for oral use.
Ismail, Ruba; Phan, Thi Nhu Quynh; Laffleur, Flavia; Csóka, Ildikó; Bernkop-Schnürch, Andreas · Pharmaceutical Formulation + Animal Pharmacokinetics
The K10H16 fusion peptide delivers functional enzymes to intracellular lysosomes via electrostatic complexation, restoring normal cell growth in lysosomal storage disease cells.
Iwasaki, Takashi; Murakami, Nodoka; Kawano, Tsuyoshi · In Vitro (Proof Of Concept)
The team created a multi-part nanocomplex that co-delivers a melanoma antigen peptide (Trp2) and a toll-like receptor 7 agonist (R837) to dendritic cells. Both ingredients dissolve poorly in water, which has made combined delivery difficult until now. They used a sugar-coated cyclodextrin shell to carry R837 and target mannose receptors on dendritic cells. A fusion peptide combined Trp2 with a cell-penetrating sequence (TAT) to help it get inside cells. Sodium alginate wrapped everything together and added its own immune-boosting effect. The nanocomplex improved cellular uptake and significantly increased the release of Th1 cytokines, which are signals linked to anti-tumor immunity.
Ji, Zhonghua; Tan, Zeng; Li, Min; Tao, Jin; Guan, Enshuang; Du, Junrong; Hu, Ying · In Vitro
The SIWV peptide was identified from an isoform of annexin-A3, a human membrane-interacting protein. It showed remarkable specificity for glioblastoma tissue both in cell cultures and in living mice. The peptide enters cells through a caveolin-mediated endocytosis pathway, confirmed through receptor inhibition and genetic knockdown experiments. When grafted onto porous silicon nanoparticles loaded with the cancer drug SN-38, SIWV-targeted nanoparticles showed significantly better tumor targeting than scrambled-peptide controls in a mouse brain tumor model. The treatment also showed statistically significant anti-tumor efficacy (P < 0.05) compared to free SN-38.
Kang, Rae Hyung; Jang, Jeong-Eun; Huh, Eugene; Kang, Seong Jae; Ahn, Dae-Ro; Kang, Jae Seung; Sailor, Michael J; Yeo, Seung Geun; Oh, Myung Sook; Kim, Dokyoung; Kim, Hyo Young · Animal Study
Penetratin enhanced the delivery of salmon calcitonin (sCT) through both TR146 buccal cell layers and porcine buccal tissues in a concentration-dependent manner. FITC-labeled Penetratin showed rapid intracellular uptake at low concentrations (0-15 micromolar) with a more gradual increase above 15 micromolar. The uptake of sCT increased alongside Penetratin concentration. At 12.2 micromolar, Penetratin enhanced sCT flux 5.5-fold through TR146 cell layers and 93.7-fold through porcine buccal tissue. The dramatically higher enhancement in actual tissue suggests Penetratin works particularly well in the multi-layered environment of real buccal mucosa.
Keum, Taekwang; Noh, Gyubin; Seo, Jo-Eun; Bashyal, Santosh; Lee, Sangkil · In Vitro
Cell-penetrating peptides must escape endosomes to deliver cargo to the cytoplasm. The researchers found that some CPP delivery protocols activate three cellular stress responses: Chmp1b (endosomal repair), Galectin-3 (organelle clearance), and TFEB (biogenesis). These same protocols also modulated endocytosis rates and endocytic proteolysis, suggesting that some CPPs disrupt normal cell trafficking. Remarkably, a multimeric analogue of TAT (the most commonly used CPP) achieved efficient endosomal escape without triggering any of these membrane damage responses. This challenges the assumption that endosomal leakiness equals toxicity and shows that clean cytoplasmic delivery is achievable.
Kondow-McConaghy, Helena M; Muthukrishnan, Nandhini; Erazo-Oliveras, Alfredo; Najjar, Kristina; Juliano, Rudolph L; Pellois, Jean-Philippe · In Vitro
Many drugs fail because they are broken down too quickly by enzymes or cannot get inside cells where they need to work. PEGylation addresses the first problem by shielding molecules from degradation and kidney clearance. CPPs address the second by ferrying cargo across cell membranes. However, CPPs themselves are peptides and suffer from rapid degradation. PEGylating CPPs can protect them while preserving their cell-penetrating ability. The review covers PEGylated CPP formulations used in drug delivery for cancer, gene therapy, protein delivery, and other biomedical applications. It discusses the trade-offs between PEG chain length, CPP type, and overall delivery efficiency.
Kumar, Sumit; Singh, Devender; Kumari, Pooja; Malik, Rajender Singh; Poonam; Parang, Keykavous; Tiwari, Rakesh Kumar · Review
PAMAM dendrimer nanoparticles decorated with both TAIP (anti-inflammatory peptide) and CPP (cell-penetrating peptide) improved mortality and organ damage in septic mice.
Lee, Wonhwa; Park, Eun Ji; Kwon, Oh Kwang; Kim, Hyelim; Yoo, Youngbum; Kim, Shin-Woo; Seo, Young-Kyo; Kim, In-San; Na, Dong Hee; Bae, Jong-Sup · Animal Study
GALA3 enhanced the cytotoxicity of BLF1-HBP fusion protein by at least 20-fold across H460, HeLa, A549, and SMCC-7721 cancer cell lines via pH-dependent endosomal escape.
Li, Chen; Cao, Xue-Wei; Zhao, Jian; Wang, Fu-Jun · In Vitro
FA-VP5-LNPs achieved 30.71-fold higher oral bioavailability (AUC0-72h) than free VP5 peptide and sustained antihypertensive effects for 6 days.
Li, Jinhua; Chen, Bin; Yu, Ting; Guo, Mengran; Zhao, Shengnan; Zhang, Yi; Jin, Chaohui; Peng, Xingchen; Zeng, Jun; Yang, Jian; Song, Xiangrong · Animal Study
Cationic oligoproline Z8 binds InsP6 with high affinity, undergoes a PPII-helix-to-aggregate conformational change, and delivers InsP6 to the nucleus more effectively than octaarginine.
Li, Mao; Puschmann, Robert; Herdlitschka, Andreas; Fiedler, Dorothea; Wennemers, Helma · In Vitro
P-D-R8MTS completely prevented lung metastasis in 4T1-bearing mice while inhibiting tumor growth, by delivering doxorubicin to mitochondria and downregulating MMP-2, VEGF, and TGF-β.
Li, Qiuyi; Yang, Jiatao; Chen, Cheng; Lin, Xi; Zhou, Minglu; Zhou, Zhou; Huang, Yuan · Animal Study
Hydrocarbon-stapled Tat peptides showed correlated improvements in helicity, hydrophobicity, heparan sulfate binding, cellular uptake, endosomal escape, and proteolytic stability with low cytotoxicity.
Li, Shu; Zhang, Xingjiao; Guo, Chen; Peng, Yali; Liu, Xiaojing; Wang, Bo; Zhuang, Ran; Chang, Min; Wang, Rui · In Vitro
Triple-peptide pH-responsive nanoparticles co-delivering irinotecan and miR-200 outperformed Onivyde in a head and neck cancer mouse model by simultaneously targeting EMT, MDR, and Wnt pathways.
Lo, Yu-Li; Chang, Chih-Hsien; Wang, Chen-Shen; Yang, Muh-Hwa; Lin, Anya Maan-Yuh; Hong, Ci-Jheng; Tseng, Wei-Hsuan · Animal
SNP-7/8a self-assembled nanoparticles induced CD8 T cells against ~50% of high-affinity predicted neoantigens (179 tested) and enhanced tumor clearance in three mouse models, with immunogenicity confirmed in primates.
Lynn, Geoffrey M; Sedlik, Christine; Baharom, Faezzah; Zhu, Yaling; Ramirez-Valdez, Ramiro A; Coble, Vincent L; Tobin, Kennedy; Nichols, Sarah R; Itzkowitz, Yaakov; Zaidi, Neeha; Gammon, Joshua M; Blobel, Nicolas J; Denizeau, Jordan; de la Rochere, Philippe; Francica, Brian J; Decker, Brennan; Maciejewski, Mateusz; Cheung, Justin; Yamane, Hidehiro; Smelkinson, Margery G; Francica, Joseph R; Laga, Richard; Bernstock, Joshua D; Seymour, Leonard W; Drake, Charles G; Jewell, Christopher M; Lantz, Olivier; Piaggio, Eliane; Ishizuka, Andrew S; Seder, Robert A · Animal
Aromatic capping groups beyond Fmoc enable self-assembling peptide materials with added functions: redox responsiveness, fluorescence, and controlled drug delivery.
Martin, Adam D; Thordarson, Pall · Review
Peptide-based nanoformulations can enhance cancer treatment efficacy by improving tumor penetration, increasing circulation time, and reducing off-target toxicity when combined with conventional therapies.
Mehrotra, Neha; Kharbanda, Surender; Singh, Harpal · Review
Ara-27 achieved >99% cell-penetrating efficiency at 2 μM in human cells compared to <10% for Tat-PTD and MTS, with 8-22x higher intracellular fluorescence intensity.
Min, Sol; Kim, Kichul; Ku, Seockmo; Park, Jeong-Yoon; Seo, Jeongmin; Roh, Sangho · In Vitro
Hydrophobic amino acid linkers (FF and LL) adjacent to the photosensitizer significantly enhanced photochemical internalization efficiency in CPP-cargo-PS conjugates across multiple cargo types.
Miyoshi, Yuichi; Kadono, Maho; Okazaki, Shigetoshi; Nishimura, Ayano; Kitamatsu, Mizuki; Watanabe, Kazunori; Ohtsuki, Takashi · In Vitro
The cyclic cLK peptide delivered fragmented Runx2 into stem cells more efficiently than Tat-CPP, producing 1.2-fold greater mineralization and higher osteogenic gene expression.
Nam, So Hee; Lee, Yan; Ahn, Joon Hyung; Chung, Chun Kee; Yang, Hee-Jin; Park, Sung Bae; Jang, Sangmok · In Vitro
Anti-ftsZ PNAs completely inhibited E. faecalis growth, while CPP-conjugated anti-efaA PNAs reduced efaA gene expression and biofilm formation by 95%, with no mammalian cell toxicity.
Narenji, Hanar; Teymournejad, Omid; Rezaee, Mohammad Ahangarzadeh; Taghizadeh, Sepehr; Mehramuz, Bahareh; Aghazadeh, Mohammad; Asgharzadeh, Mohammad; Madhi, Masoumeh; Gholizadeh, Pourya; Ganbarov, Khudaverdi; Yousefi, Mehdi; Pakravan, Asrin; Dal, Tuba; Ahmadi, Raman; Samadi Kafil, Hossein · In Vitro
CPP-conjugated PNAs and siRNAs can inhibit hepatitis B virus replication and antigen expression, with CPPs solving the critical intracellular delivery challenge for oligonucleotide-based antivirals.
Ndeboko, Bénédicte; Omouessi, Serge Thierry; Ongali, Brice; Mouinga-Ondémé, Augustin · Review
Glutamic acid-templated peptide motifs (EEGGC and EEEEE) conjugated to KLD self-assembling scaffolds significantly enhanced osteogenic differentiation markers and calcium deposition in human MSCs.
Onak, Günnur; Gökmen, Oğuzhan; Yaralı, Ziyşan Buse; Karaman, Ozan · In Vitro
PAS-pHK peptide delivers miR-126 selectively to cancer cells, targeting mitochondria to induce apoptosis synergistically while showing no toxicity to non-cancerous cells.
Palanikumar, L; Al-Hosani, Sumaya; Kalmouni, Mona; Saleh, Hadi Omar; Magzoub, Mazin · In Vitro
16A-MMAE ADC targeting the GSTA glycosite-specific neoantigen peptide of MUC1 showed IC50 of 0.2-49.4 nM against cancer cells and dose-dependent tumor inhibition in vivo at 1 mg/kg minimum effective dose.
Pan, Deng; Tang, Yubo; Tong, Jiao; Xie, Chengmei; Chen, Jiaxi; Feng, Chunchao; Hwu, Patrick; Huang, Wei; Zhou, Dapeng · Animal Study
Linear PEI/pDNA polyplexes successfully transfected human keratinocytes and fibroblasts to overexpress LL-37, with supernatants reducing S. aureus growth by 95.8%.
Patiño Vargas, Maria Isabel; Mesa Cadavid, Mónica; Arenas Gómez, Claudia Marcela; Diosa Arango, Johnatan; Restrepo Múnera, Luz Marina; Becerra Colorado, Natalia Yiset · In Vitro
All synthesized penetratin analogues demonstrated measurable trans-corneal diffusion despite their hydrophilic nature and ~1.6 kDa size, though none achieved the penetration efficiency of full-length penetratin.
Pescina, Silvia; Sala, Marina; Scala, Maria Carmina; Santi, Patrizia; Padula, Cristina; Campiglia, Pietro; Ostacolo, Carmine; Nicoli, Sara · In Vitro
Smac-CPP nanoparticles combined with doxorubicin reduced tumor growth by 85% in vivo, with decreased Ki-67 proliferation staining and increased cleaved caspase-3 apoptosis staining in tumors.
Priwitaningrum, Dwi L; Jentsch, Julian; Bansal, Ruchi; Rahimian, Sima; Storm, Gert; Hennink, Wim E; Prakash, Jai · Animal Study
INH-CPP conjugates showed conjugation-induced structural and membrane interaction changes that correlated with each other; Penetratin and Transportan conjugates had similar cell uptake but different subcellular localization and anti-Mtb activity.
Pári, Edit; Horváti, Kata; Bősze, Szilvia; Biri-Kovács, Beáta; Szeder, Bálint; Zsila, Ferenc; Kiss, Éva · In Vitro
The adamantane/β-cyclodextrin host-guest pair successfully anchored RGDS epitopes onto peptide amphiphile hydrogels via noncovalent interactions, supporting fibroblast attachment, organization, and spreading while maintaining hydrogel structural properties.
Redondo-Gómez, Carlos; Padilla-Lopategui, Soraya; Azevedo, Helena S; Mata, Alvaro · In Vitro
CPPs escape endosomes through a budding-and-collapse mechanism: CPP-enriched vesicles bud from the endosomal membrane and subsequently collapse, releasing cargo into the cytosol.
Sahni, Ashweta; Qian, Ziqing; Pei, Dehua · In Vitro
Smaller vesicles suppressed CPP cytolysis despite higher membrane curvature, because reduced lipid mobility in smaller vesicles restricts the local phase transitions required for CPP membrane penetration.
Sakamoto, Kazutami; Kitano, Takeshi; Kuwahara, Haruka; Tedani, Megumi; Aburai, Kenichi; Futaki, Shiroh; Abe, Masahiko; Sakai, Hideki; Ohtaka, Hiroyasu; Yamashita, Yuji · In Vitro
CPP cytolysis occurs in two steps: rapid adsorption (saturated within 10 min) followed by linear-rate internalization dependent on osmotic pressure. The mechanism involves Lα to Mesh1 lipid phase transition creating punctured bilayer morphologies.
Sakamoto, Kazutami; Morishita, Taku; Aburai, Kenichi; Sakai, Kenichi; Abe, Masahiko; Nakase, Ikuhiko; Futaki, Shiroh; Sakai, Hideki · In Vitro
tCPP conjugation achieved up to 4-fold elevated internalization rates for three clinical antibodies while retaining target specificity. tCPP-Kadcyla showed 6-fold increased cytotoxicity. Favorable pharmacokinetics limited off-target accumulation.
Sauter, Max; Strieker, Matthias; Kleist, Christian; Wischnjow, Artjom; Daniel, Volker; Altmann, Annette; Haberkorn, Uwe; Mier, Walter · In Vitro