Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been on a rampage for more than two years. Vaccines in combination with neutralizing antibodies (NAbs) against SARS-CoV-2 carry great hope in the treatment and final elimination of coronavirus disease 2019 (COVID-19). However, the relentless emergence of variants of concern (VOC), including the most recent Omicron variants, presses for novel measures to counter these variants that often show immune evasion. Hereby we developed a targeted photodynamic approach to neutralize SARS-CoV-2 by engineering a genetically encoded photosensitizer (SOPP3) to a diverse list of antibodies targeting the wild-type (WT) spike protein, including human antibodies isolated from a 2003 Severe acute respiratory syndrome (SARS) patient, potent monomeric and multimeric nanobodies targeting receptor-binding domain (RBD), and non-neutralizing antibodies (non-NAbs) targeting the more conserved N-terminal domain (NTD). As confirmed by pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, especially that of non-NAbs, against not only the WT but also the Delta strain and the heavily immune escape Omicron strain (BA.1). Subsequent measurement of infrared phosphorescence at 1270 nm confirmed the generation of singlet oxygen ( 1 O 2 ) in the photodynamic process. Mass spectroscopy assay uncovered amino acids in the spike protein targeted by 1 O 2 . Impressively, Y145 and H146 form an oxidization “hotspot”, which overlaps with the antigenic “supersite” in NTD. Taken together, our study established a targeted photodynamic approach against the SARS-CoV-2 virus and provided mechanistic insights into the photodynamic modification of protein molecules mediated by 1 O 2 . Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s43630-023-00381-w.