The emergence of new SARS-CoV-2 variants made the COVID-19 infection pandemic and/or endemic more severe and life-threatening due to ease of transmission, rapid infection, high mortality, and capacity to neutralize the therapeutic ability of developed vaccines. These consequences raise questions on established COVID-19 infection management strategies based on nano-assisted approaches, including rapid diagnostics, therapeutics, and efficient trapping and virus eradication through stimuli-assisted masks and filters composed of nanosystems. Considering these concerns as motivation, this perspective article highlights the role and aspects of nano-enabled approaches to manage the consequences of the COVID-19 infection pandemic associated with newer SARS-CoV-2 variants of concern and significance generated due to mutations. The controlled high-performance of a nanosystem seems capable of effectively detecting new variables for rapid diagnostics, performing site-specific delivery of a therapeutic agent needed for effective treatment, and developing technologies to purify the air and sanitizing premises. The outcomes of this report project manipulative, multifunctional nanosystems for developing high-performance technologies needed to manage consequences of newer SARS-CoV-2 variants efficiently and effectively through an overall targeted, smart approach.