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Next-Generation Targeted Therapy: vNARs, VHH, and Peptides as Drug Carriers...
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Next-Generation Targeted Therapy: vNARs, VHH, and Peptides as Drug Carriers and Intracellular Neutralizing Agents

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 20 October 2026 | Viewed by 956

Special Issue Editors

Dr. Tanya Camacho-Villegas

E-Mail Website
Guest Editor
Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara C.P. 44270, Jalisco, Mexico
Interests: immunology; antibodies; single domains; recombinant proteins; molecular biology; biomedicine
Dr. Mirna Burciaga-Flores

E-Mail Website
Guest Editor
Centro de Nanociencias y Nanotecnología, Universidad Nacional Autónoma de México (CNyN-UNAM), Carretera Tijuana-Ensenada km107, Ensenada C.P. 22860, Baja California, Mexico
Interests: immunotherapy; vaccine; drug carrier; antibody

Special Issue Information

Dear Colleagues,

vNAR single-domain antibodies, originally isolated from sharks, are emerging as transformative tools for drug delivery and intracellular neutralization in human diseases. These naturally occurring antibody domains possess antigen-recognition capacity and exhibit distinctive properties, including compact size (approximately 12-15 kDa), exceptional thermal and chemical stability, high affinity, high solubility, the ability to access cryptic epitopes, and potential for humanization. These attributes offer significant opportunities for the application of vNARs in drug delivery and intracellular neutralization across multiple scientific fields, including nanotechnology, biomedicine, biosensing, intrabodies, payload delivery, and imaging. In addition, VHHs isolated from camelids share characteristics with vNARs but are more like mammalian antibodies. Peptides, as smaller binding ligands, offer enhanced tissue penetration and clearance, supporting their use in intracellular neutralization.

The high affinities, selectivities, and small sizes of vNARs, VHHs, and peptides facilitate the active targeting of nanoparticles, nanosystems, and lipidic vesicles (such as exosomes and liposomes), as well as amino acid sequences that enhance the delivery of drugs, chemosensitizers, radioactive agents, or therapeutic proteins.

Research on vNARs, VHHs, and peptides as intrabodies or intracellular targeting agents with neutralization capabilities is particularly significant. Key areas of investigation include cancer, cell membrane interactions, cell adhesion molecules, cytosolic delivery, mitochondrial targeting, cell cycle checkpoint proteins, immunotherapy checkpoint inhibitors, immunomodulators, and tumor-targeting peptides (TTPs), among others.

Collaborative efforts are crucial to fully realize the therapeutic and diagnostic potential of vNARs and VHHs as single-domain antibodies or peptides, thereby advancing global health and biomedical science.

We invite authors to submit comprehensive reviews and original breakthrough research articles that elucidate and advance the application of vNARs, VHHs, and peptides as intracellular neutralizing agents.

Dr. Tanya Camacho-Villegas
Dr. Mirna Burciaga-Flores
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vNAR
  • VHH
  • peptides
  • drug delivery
  • intrabodies
  • payload
  • nanotechnology
  • immunotoxins
  • phage display
  • biopanning
  • single domain antibody
  • neutralizing agents
  • intracellular targeting

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Published Papers (1 paper)

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Research

23 pages, 3353 KB  
Article
Theranostic vNAR-Based Immunoconjugates Achieve Selective Intracellular Cisplatin Delivery in Embedded 3D HER2-Positive Breast Cancer In Vitro Model
by Andrea C. Alfonseca-Ladrón de Guevara, Alejandro Manzanares-Guzmán, Jessica A. Badillo-Mata, Mirna Burciaga-Flores, Pavel H. Lugo-Fabres and Tanya A. Camacho-Villegas
Pharmaceuticals 2026, 19(4), 633; https://doi.org/10.3390/ph19040633 - 17 Apr 2026
Viewed by 395
Abstract
Background/Objectives: Precise intracellular delivery of chemotherapeutics remains a major challenge in HER2-positive breast cancer, where intratumoral heterogeneity and limited tissue penetration constrain efficacy. A key contributor is the tumor-restricted epidermal growth factor receptor variant III (EGFRvIII), a constitutively active, ligand-independent mutant generated [...] Read more.
Background/Objectives: Precise intracellular delivery of chemotherapeutics remains a major challenge in HER2-positive breast cancer, where intratumoral heterogeneity and limited tissue penetration constrain efficacy. A key contributor is the tumor-restricted epidermal growth factor receptor variant III (EGFRvIII), a constitutively active, ligand-independent mutant generated by deletion of exons 2–7. Although classically associated with glioblastoma, lung (NSCLC), head/neck, and prostate cancers, EGFRvIII is also present in subsets of HER2-positive breast cancers, where low-abundance subclones drive aggressive phenotypes and attenuate therapeutic responses. HER2–EGFRvIII co-expression amplifies oncogenic signaling, supported by frequent co-expression in ErbB2-positive primary tumors and metastases, and by sustained receptor phosphorylation in the absence of EGFR gene amplification, depicting EGFRvIII as a compelling therapeutic target. Methods: We evaluated the shark-derived single-domain antibody vNAR R426 as a modular theranostic platform for receptor-mediated cisplatin delivery. Conjugation to cisplatin and fluorescein enabled simultaneous intracellular drug transport and immunofluorescence-based detection in EGFRvIII-positive SKBR3 cells and 3D spheroids. The compact vNAR-based immunoconjugates support efficient receptor recognition, internalization, and intracellular trafficking, features rarely achieved by conventional IgG antibodies. Results: vNARCDDP elicited robust, receptor-mediated cytotoxicity, achieving an IC50 of 2.68 µM—approximately 50-fold lower than that of free cisplatin—while unconjugated vNAR maintained scaffold biocompatibility. In three-dimensional spheroid models, the theranostic vNAR (vNARCDDP+FITC) exhibited deep and uniform penetration throughout tumor-like architectures, with immunofluorescence intensity closely correlating with regions of intracellular drug delivery and the initiation of cytotoxic responses. Notably, cisplatin conjugation did not impair tissue diffusion or receptor engagement, facilitating effective payload delivery to both peripheral and central cell populations. Conclusions: By integrating tumor-restricted targeting and efficient intracellular drug delivery within a modular single-domain scaffold, vNAR R426 represents a next-generation theranostic platform capable of addressing intratumoral heterogeneity. This approach combines potent cytotoxic activity with immunofluorescence-based detection, thereby advancing the rational design of precision therapeutics for HER2-positive breast cancer. Full article
(This article belongs to the Special Issue Next-Generation Targeted Therapy: vNARs, VHH, and Peptides as Drug Carriers and Intracellular Neutralizing Agents)
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