Review Article Review: Development of SARS-CoV-2 immuno-enhanced COVID- 19 vaccines with nano-platform Nawamin Sa-nguanmoo 1,2 , Katawut Namdee 3 , Mattaka Khongkow 3 , Uracha Ruktanonchai 3 , YongXiang Zhao 4 , and Xing-Jie Liang 1,2 ( ✉ ) 1  CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China 2  University of Chinese Academy of Sciences, Beijing 100049, China 3  National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency, Pathum Thani 12120, Thailand 4  National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumour Theranostics and Therapy, Guangxi Medical University, Nanning 530021, China © Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021 Received: 24 June 2021 / Revised: 19 August 2021 / Accepted: 19 August 2021 ABSTRACT Vaccination is the most effective way to prevent coronavirus disease 2019 (COVID-19). Vaccine development approaches consist of viral vector vaccines, DNA vaccine, RNA vaccine, live attenuated virus, and recombinant proteins, which elicit a specific immune response. The use of nanoparticles displaying antigen is one of the alternative approaches to conventional vaccines. This is due to the fact that nano-based vaccines are stable, able to target, form images, and offer an opportunity to enhance the immune responses. The diameters of ultrafine nanoparticles are in the range of 1–100 nm. The application of nanotechnology on vaccine design provides precise fabrication of nanomaterials with desirable properties and ability to eliminate undesirable features. To be successful, nanomaterials must be uptaken into the cell, especially into the target and able to modulate cellular functions at the subcellular levels. The advantages of nano-based vaccines are the ability to protect a cargo such as RNA, DNA, protein, or synthesis substance and have enhanced stability in a broad range of pH, ambient temperatures, and humidity for long-term storage. Moreover, nano-based vaccines can be engineered to overcome biological barriers such as nonspecific distribution in order to elicit functions in antigen presenting cells. In this review, we will summarize on the developing COVID-19 vaccine strategies and how the nanotechnology can enhance antigen presentation and strong immunogenicity using advanced technology in nanocarrier to deliver antigens. The discussion about their safe, effective, and affordable vaccines to immunize against COVID-19 will be highlighted. KEYWORDS COVID-19, SARS-CoV-2, vaccine, nanotechnology, antigen presenting cells (APCs)   1    Introduction The seventh β-coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was firstly reported on Dec. 2019 at Wuhan, China. Previously, αCoV (HCoV-229E and HKU-NL63) and four types of βCoV (HCoV-OC43, HCoV-HKU1, SARS- CoV, and MERS-CoV) were discovered. The SARS-CoV-2 causes symptoms in the upper respiratory and gastrointestinal tracts. Phylogenetic analysis has revealed that SARS-CoV-2 has four amino acids (PRRA) insert at the edge of S1 and S2 which add the new functional furin cleavage site and improve the ability of the SARS-CoV-2 for binding to enzyme 2 (ACE2) receptor (Fig. 1). The disease from SARS-CoV-2 was named as “coronavirus disease 2019 (COVID-19)” by the World Health Organization (WHO) on 11 February 2020. SARS-CoV-2 has an ancestor sequence derived from bat-CoV-RaTG13. The virus in the bat contains the amino acids polyacrylic acid (PAA) by recombination of sequences that derived from RmYN02 in Rhinolophus malayanus bat. However, the receptor-binding domain (RBD) of SARS-CoV-2 is similar to beta-CoVs in Malayan pangolins (Manis javanica). Major challenges in designing effective vaccines with minimal adverse effects are to fully understand the virus and how our body stimulates the immune responses. The candidate COVID-19 vaccines in clinical trial consist of the conventional development approach (inactivated virus, viral-based vaccine) and the modern development using nanotechnology platform (nucleic acid-based, protein-based vaccine). Both approaches elicit an immune response and prevent COVID-19. However, common limitations of the conventional vaccines include being administered mainly through parenteral routes and requiring multiple doses [1], cold-chain maintenance that needs to be kept at +2 to +8 °C to ensure vaccine potency [2], potential risk of virus- based vaccine localization in the central nervous system [3], and taking many years for safety and efficacy approval [4]. The accelerating vaccine development and deployment to combat SARS-CoV-2 by using modern strategies such as nanoparticle formulated vaccines and the evaluation are urgently needed [5–7]. Nanotechnology was first applied in medicine to increase the efficacy and bioavailability of drugs in 2005 [8]. It plays an important role on vaccine design and applications. It truly ISSN 1998-0124 CN 11-5974/O4 https://doi.org/10.1007/s12274-021-3832-y   Address correspondence to liangxj@nanoctr.cn