---
title: "VEGF-A siRNA-loaded Nanocarriers for Anti‑angiogenic Cancer Therapy: Advances and Challenges"
id: "pubmed-42521061"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42521061"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42521061/"
doi: "10.1016/j.ijpharm.2026.127251"
published_at: "2026-09-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# VEGF-A siRNA-loaded Nanocarriers for Anti‑angiogenic Cancer Therapy: Advances and Challenges
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42521061
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42521061/)
- **DOI:** [10.1016/j.ijpharm.2026.127251](https://doi.org/10.1016%2Fj.ijpharm.2026.127251)
- **Published At:** 2026-09-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Angiogenesis is a core process in solid tumor progression and is primarily regulated by **VEGF‑A**, which promotes tumor vascularization, immune suppression, and therapeutic resistance. - Existing VEGF-targeting therapies (monoclonal antibodies, tyrosine kinase inhibitors) show clinical benefit but are limited by adaptive resistance, systemic toxicity, and incomplete VEGF signaling suppression. - **siRNA-mediated silencing of VEGF‑A (siVEGF‑A)** enables gene-specific inhibition at the mRNA level but faces delivery hurdles: rapid nuclease degradation, poor cellular uptake, and endosomal entrapment. - The review examines multiple **nanocarrier** platforms for siVEGF‑A delivery: lipid nanoparticles, polymeric and dendrimer carriers, inorganic platforms, biomimetic systems, and hybrid nanostructures. - Preclinical studies across cancer models report consistent VEGF knockdown, typically in the range of **60–80%**, with correlated reductions in tumor microvessel density and significant tumor growth inhibition. - Co‑delivery strategies that combine siVEGF‑A with chemotherapeutics (examples: **doxorubicin**, **irinotecan**) enhance antitumor efficacy by both suppressing angiogenesis and sensitizing tumors to cytotoxic agents. - Persistent translational barriers include formulation stability, biodistribution, immune activation, inefficient endosomal escape, and challenges in scalable manufacturing. - The review synthesizes mechanistic insights, therapeutic outcomes, and translational limitations to outline design principles and future directions for clinically translating VEGF‑A siRNA‑loaded nanocarriers.
## Clinical Analysis & Structured Key Points
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Epub 2026 Jul 28. # Targeting tumor angiogenesis: advances in VEGF-A siRNA-loaded nanocarriers for anti-angiogenic cancer therapy [Rishabh Aggarwal](https://pubmed.ncbi.nlm.nih.gov/?term=Aggarwal+R&cauthor_id=42521061)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-1 "Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India."), [Urushi Rehman](https://pubmed.ncbi.nlm.nih.gov/?term=Rehman+U&cauthor_id=42521061)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-1 "Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India."), [Shivam Gupta](https://pubmed.ncbi.nlm.nih.gov/?term=Gupta+S&cauthor_id=42521061)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-2 "Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India."), [Ramasubbamma Ramaiah](https://pubmed.ncbi.nlm.nih.gov/?term=Ramaiah+R&cauthor_id=42521061)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-3 "Department of Medical and Surgical Nursing, College of Nursing, Khamish Mushait, King Khalid University, Female Wing, Mahala Road, Abha, Saudi Arabia."), [Umme Hani](https://pubmed.ncbi.nlm.nih.gov/?term=Hani+U&cauthor_id=42521061)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-4 "Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia."), [Garima Gupta](https://pubmed.ncbi.nlm.nih.gov/?term=Gupta+G&cauthor_id=42521061)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-5 "Central Research Facility, Dr. D Y Patil Medical College Hospital and Research Centre, Dr. D Y Patil Vidyapeeth \(Deemed to be University\), Pimpri, Pune, India; School of Allied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India."), [Khang Wen Goh](https://pubmed.ncbi.nlm.nih.gov/?term=Goh+KW&cauthor_id=42521061)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-6 "Faculty of Business and Communication, INTI International University, Nilai, Malaysia."), [Prashant Kesharwani](https://pubmed.ncbi.nlm.nih.gov/?term=Kesharwani+P&cauthor_id=42521061)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#full-view-affiliation-7 "Next-Generation Translational Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya \(A Central University\), Sagar, Madhya Pradesh 470003, India; Department of Research and Development, Asia University, Taichung, Taiwan. Electronic address: prashantdops@gmail.com.") Affiliations Expand ### Affiliations * 1 Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. * 2 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. * 3 Department of Medical and Surgical Nursing, College of Nursing, Khamish Mushait, King Khalid University, Female Wing, Mahala Road, Abha, Saudi Arabia. * 4 Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia. * 5 Central Research Facility, Dr. D Y Patil Medical College Hospital and Research Centre, Dr. D Y Patil Vidyapeeth (Deemed to be University), Pimpri, Pune, India; School of Allied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India. * 6 Faculty of Business and Communication, INTI International University, Nilai, Malaysia. * 7 Next-Generation Translational Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh 470003, India; Department of Research and Development, Asia University, Taichung, Taiwan. Electronic address: prashantdops@gmail.com. * PMID: **42521061** * DOI: [ 10.1016/j.ijpharm.2026.127251 ](https://doi.org/10.1016/j.ijpharm.2026.127251) Item in Clipboard Review # Targeting tumor angiogenesis: advances in VEGF-A siRNA-loaded nanocarriers for anti-angiogenic cancer therapy Rishabh Aggarwal et al. Int J Pharm. 2026. Show details Display options Display options Format Abstract PubMed PMID Int J Pharm Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Int+J+Pharm%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Int+J+Pharm%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42521061/) . 2026 Sep 5:702:127251. doi: 10.1016/j.ijpharm.2026.127251. Epub 2026 Jul 28. ### Authors [Rishabh Aggarwal](https://pubmed.ncbi.nlm.nih.gov/?term=Aggarwal+R&cauthor_id=42521061)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-1 "Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India."), [Urushi Rehman](https://pubmed.ncbi.nlm.nih.gov/?term=Rehman+U&cauthor_id=42521061)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-1 "Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India."), [Shivam Gupta](https://pubmed.ncbi.nlm.nih.gov/?term=Gupta+S&cauthor_id=42521061)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-2 "Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India."), [Ramasubbamma Ramaiah](https://pubmed.ncbi.nlm.nih.gov/?term=Ramaiah+R&cauthor_id=42521061)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-3 "Department of Medical and Surgical Nursing, College of Nursing, Khamish Mushait, King Khalid University, Female Wing, Mahala Road, Abha, Saudi Arabia."), [Umme Hani](https://pubmed.ncbi.nlm.nih.gov/?term=Hani+U&cauthor_id=42521061)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-4 "Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia."), [Garima Gupta](https://pubmed.ncbi.nlm.nih.gov/?term=Gupta+G&cauthor_id=42521061)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-5 "Central Research Facility, Dr. D Y Patil Medical College Hospital and Research Centre, Dr. D Y Patil Vidyapeeth \(Deemed to be University\), Pimpri, Pune, India; School of Allied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India."), [Khang Wen Goh](https://pubmed.ncbi.nlm.nih.gov/?term=Goh+KW&cauthor_id=42521061)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-6 "Faculty of Business and Communication, INTI International University, Nilai, Malaysia."), [Prashant Kesharwani](https://pubmed.ncbi.nlm.nih.gov/?term=Kesharwani+P&cauthor_id=42521061)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42521061/#short-view-affiliation-7 "Next-Generation Translational Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya \(A Central University\), Sagar, Madhya Pradesh 470003, India; Department of Research and Development, Asia University, Taichung, Taiwan. Electronic address: prashantdops@gmail.com.") ### Affiliations * 1 Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. * 2 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. * 3 Department of Medical and Surgical Nursing, College of Nursing, Khamish Mushait, King Khalid University, Female Wing, Mahala Road, Abha, Saudi Arabia. * 4 Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia. * 5 Central Research Facility, Dr. D Y Patil Medical College Hospital and Research Centre, Dr. D Y Patil Vidyapeeth (Deemed to be University), Pimpri, Pune, India; School of Allied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India. * 6 Faculty of Business and Communication, INTI International University, Nilai, Malaysia. * 7 Next-Generation Translational Nanomedicine Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh 470003, India; Department of Research and Development, Asia University, Taichung, Taiwan. Electronic address: prashantdops@gmail.com. * PMID: **42521061** * DOI: [ 10.1016/j.ijpharm.2026.127251 ](https://doi.org/10.1016/j.ijpharm.2026.127251) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Angiogenesis is a fundamental hallmark of solid tumor progression, with vascular endothelial growth factor-A (VEGF-A) serving as a central regulator of tumor vascularization, immune suppression, and therapeutic resistance. Although monoclonal antibodies and tyrosine kinase inhibitors targeting VEGF have demonstrated clinical benefit, their efficacy is frequently limited by adaptive resistance, systemic toxicity, and incomplete suppression of VEGF signaling. Small interfering RNA (siRNA)-mediated silencing of vascular endothelial growth factor-A (VEGF-A), the predominant pro-angiogenic isoform in cancer, offers a gene-specific strategy capable of inhibiting angiogenesis at the mRNA level; however, its clinical translation is constrained by rapid nuclease degradation, poor cellular uptake, and endosomal entrapment. This review critically examines nanocarrier-based delivery systems developed for VEGF-A-targeted siRNA (siVEGF-A), including lipid nanoparticles, polymeric and dendrimer-based carriers, inorganic platforms, biomimetic systems, and hybrid nanostructures. Across multiple preclinical cancer models, these systems consistently achieve substantial VEGF knockdown (typically 60-80%), leading to marked reductions in tumor microvessel density and significant tumor growth inhibition. Co-delivery strategies integrating siVEGF-A with chemotherapeutic agents such as doxorubicin or irinotecan further enhance antitumor efficacy by synergistically suppressing angiogenesis while sensitizing tumours to cytotoxic therapy. Despite encouraging preclinical outcomes, challenges related to formulation stability, biodistribution, immune activation, endosomal escape efficiency, and scalable manufacturing remain major barriers to clinical translation. By synthesizing mechanistic insights, therapeutic outcomes, and translational limitations, this review highlights key design principles and future directions for the development and clinical translation of VEGF-A siRNA-loaded nanocarriers for anti-angiogenic cancer therapy. **Keywords:** Angiogenesis inhibition; Nanocarriers; RNA interference (RNAi); Targeted cancer therapy; VEGF-A-siRNA. Copyright © 2026 Elsevier B.V. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ Extracellular vesicles derived from dendritic cells loaded with VEGF-A siRNA and doxorubicin reduce glioma angiogenesis in vitro. ](https://pubmed.ncbi.nlm.nih.gov/38522817/) Shamshiripour P, Rahnama M, Nikoobakht M, Rad VF, Moradi AR, Ahmadvand D.Shamshiripour P, et al.J Control Release. 2024 May;369:128-145. doi: 10.1016/j.jconrel.2024.03.042. Epub 2024 Mar 26.J Control Release. 2024.PMID: 38522817 * [ Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab. ](https://pubmed.ncbi.nlm.nih.gov/20052738/) Höbel S, Koburger I, John M, Czubayko F, Hadwiger P, Vornlocher HP, Aigner A.Höbel S, et al.J Gene Med. 2010 Mar;12(3):287-300. doi: 10.1002/jgm.1431.J Gene Med. 2010.PMID: 20052738 * [ Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect _via_ Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment. ](https://pubmed.ncbi.nlm.nih.gov/31534526/) Li F, Wang Y, Chen WL, Wang DD, Zhou YJ, You BG, Liu Y, Qu CX, Yang SD, Chen MT, Zhang XN.Li F, et al.Theranostics. 2019 Aug 12;9(20):5886-5898. doi: 10.7150/thno.32416. eCollection 2019.Theranostics. 2019.PMID: 31534526Free PMC article. * [ Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. ](https://pubmed.ncbi.nlm.nih.gov/26001391/) Zhao Y, Adjei AA.Zhao Y, et al.Oncologist. 2015 Jun;20(6):660-73. doi: 10.1634/theoncologist.2014-0465. Epub 2015 May 22.Oncologist. 2015.PMID: 26001391Free PMC article.Review. * [ Nanocarrier-based delivery of siRNA therapeutics in rheumatoid arthritis: immune mechanisms and translational perspectives. ](https://pubmed.ncbi.nlm.nih.gov/41425586/) Bai L, Su P.Bai L, et al.Front Immunol. 2025 Dec 17;16:1718256. doi: 10.3389/fimmu.2025.1718256. eCollection 2025.Front Immunol. 2025.PMID: 41425586Free PMC article.Review. [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42521061) ## Publication types *
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