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We recently demonstrated a form of interferometric scattering microscopy called Photonic Resonator Interferometric Scattering Microscopy (PRISM) that amplifies the contrast of surface-attached nano-objects via a photonic crystal (PC) surface. Recently, our team also developed net-shaped DNA nanostructures called \u201cDesigner DNA Nets\u201d (DDN) that organize multivalent aptamer arrays to precisely match the pattern of proteins on the outer surface of intact virions to provide high-affinity and selective binding. In this work, we demonstrate the combination of DDNs and PRISM for detection of HIV by digital counting of captured viruses. We compare multivalent DDN-based viral capture to monomeric aptamer and nanobody capture, in which the captured virions are tethered to the PC surface by a DNA linker. We observe that tethered virions are not fully stationary and that their localized dynamic movement provides a route for label-free digital-resolution detection with a signal-to-noise ratio of 50, while disregarding the presence of image features not related to specific virus capture. We obtain a detection limit of 104\u2009virions\/ml with a single-step, room temperature 30-min assay and excellent selectivity for non-detection of a nonspecific virus and the presence of a high concentration of extracellular vesicles. This study highlights PRISM's utility as a means for versatile detection of immobilized particles as part of an assay for affinity molecule evaluation.<\/jats:p>","DOI":"10.1063\/5.0289982","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T12:54:03Z","timestamp":1775048043000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Selective capture and digital counting of intact HIV pseudovirus using designer DNA nets, tethered motion, and photonic resonator interferometric scattering microscopy"],"prefix":"10.1063","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-9778","authenticated-orcid":false,"given":"Joseph","family":"Tibbs","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Illinois Urbana-Champaign 1 , Urbana, Illinois 61801,","place":["USA"]},{"name":"Nick Holonyak Jr. Micro and Nanotechnology Laboratory (HMNTL), University of Illinois Urbana-Champaign 2 , Urbana, Illinois 61801,","place":["USA"]},{"name":"Carl R. 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