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However, detecting low\u2010abundance biomarkers such as microRNA typically necessitates complex and costly enzyme\u2010based strategies like PCR or isothermal amplification. Here, a materials\u2010driven approach is leveraged to rationally design stimuli\u2010responsive, signal\u2010amplifying, and graphically\u2010encoded hydrogel microparticles, termed Novabeads, for enzyme\u2010free and fluorescence\u2010based biomarker detection. Novabeads incorporate pH\u2010responsive acrylic acid moieties within a polyethylene glycol diacrylate\u2010based network, enabling significant volume reduction (\u22485 fold) upon pH modulation. This stimuli\u2010responsive shrinking, coupled with high bioreceptor loading via thiol\u2010ene click chemistry, enables rapid, enzyme\u2010free optical signal amplification. As a proof\u2010of\u2010concept, fluorescently\u2010labeled peptide nucleic acid (PNA) probes are designed for detecting the cancer biomarker miR\u201016, via a fluorogenic F\u00f6rster resonance energy transfer (FRET)\u2010based signal. Novabeads exhibit &gt;30 fold signal enhancement over equivalent conventional hydrogel microparticles, driven by three synergistic mechanisms: increased probe loading (\u22482.6 fold), enhanced target capture (\u22482.8 fold), and shrinkage\u2010driven amplification (\u22485 fold), ultimately leading to over 7 fold reduction in detection limit (28.8 pM; 2.9 fmol), and an expanded linear dynamic range. This rationally designed materials\u2010driven biosensing strategy enables next\u2010generation robust, versatile and enzyme\u2010free biosensors for liquid biopsy diagnostics.<\/jats:p>","DOI":"10.1002\/smll.202503990","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T05:20:22Z","timestamp":1750828822000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<i>Novabeads<\/i>\n                    : Stimuli\u2010Responsive Signal\u2010Amplifying Hydrogel Microparticles for Enzymeless Fluorescence\u2010Based Detection of microRNA Biomarkers"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5250-7407","authenticated-orcid":false,"given":"Haoliang","family":"Lu","sequence":"first","affiliation":[{"name":"Division of Biological and Environmental Science and Engineering King Abdullah University of Science and Technology (KAUST)  Thuwal 23955\u20106900 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