and remdesivir to treat SARS-CoV-2 infection. [3] Meanwhile, researchers have also reported the development of effective neutralizing antibodies using techniques such as single B cell sequencing. [4] Nevertheless, one of the most promising strategies for COVID-19 prevention relies on vaccine development. There have already been more than 100 vaccines under development, including whole virus vaccines (attenuated, inactivated, or recombinant virus), subunit vaccines, DNA, and RNA vaccines. [5] For example, an inactivated SARS-CoV-2 whole virus vaccine from China showed efficacy in mice, rats, and monkeys. [6] Another recombinant adenovirus vaccine clinical trial (NCT04313127) has posted its phase 1 results with neutralizing antibodies and reported specific T cell responses. [7] Whole virus vaccines are expensive, dangerous during production, and may cause severe vaccine-related diseases. [8] Alternatively, using subunit vaccines with virus antigen protein should be a safer, more effective, and economic strategy. Recombinant expression of the antigen in organisms such as E. coli, yeast, or mammalian cells can facilitate the large-scale production. The receptor binding domain of SARS-CoV-2 spike protein (S-RBD) has been shown to mediate the entry of the virus into host cells via interacting with human angiotensin converting Prevention and intervention methods are urgently needed to curb the global pandemic of coronavirus disease-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Herein, a general pro-antigen strategy for subunit vaccine development based on the reversibly formulated receptor binding domain of SARS-CoV-2 spike protein (S-RBD) is reported. Since the poor lymph node targeting and uptake of S-RBD by antigen-presenting cells prevent effective immune responses, S-RBD protein is formulated into a reversible nanogel (S-RBD-NG), which serves as a pro-antigen with enhanced lymph node targeting and dendritic cell and macrophage accumulation. Synchronized release of S-RBD monomers from the internalized S-RBD-NG pro-antigen triggers more potent immune responses in vivo. In addition, by optimizing the adjuvant used, the potency of S-RBD-NG is further improved, which may provide a generally applicable, safer, and more effective strategy for subunit vaccine development against SARS-CoV-2 as well as other viruses.