{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:01:11Z","timestamp":1785423671929,"version":"3.56.0"},"reference-count":191,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Messenger RNA (mRNA) entered clinical medicine through vaccines, where the innate immune reactivity that complicates protein therapeutics acts as a built-in adjuvant. The success of the coronavirus disease 2019 (COVID-19) mRNA vaccines inspired an expansive vision of an mRNA 2.0 era extending the modality to rare and common diseases, with delivery framed as the principal challenge. This review accepts much of that vision but argues it rests on an unstated assumption: that all protein therapeutics form a single pharmacological class. They do not. We propose a taxonomy, the Dose\u2013Response Architecture Classification, separating two classes. Exposure-controlled therapeutics require a specific quantity of active protein on a defined regimen, as outcomes depend on reproducible exposure; examples include insulin, erythropoietin, growth hormone, coagulation factors, and narrow-therapeutic-index biologics. Threshold-response therapeutics depend on surpassing a functional threshold rather than maintaining a precise concentration; these include vaccines, many enzyme-replacement therapies, genome editing, receptor-saturating antibodies, and immune-cell reprogramming. Because an mRNA drug is dosed as an instruction, and a single message is translated into a variable number of proteins through a multiplicative, stochastic intracellular chain, the dose-to-effect relationship is inherently variable. Our central, deliberately falsifiable proposition is that mRNA is suitable for threshold-response therapeutics but unsuitable for exposure-controlled therapeutics unless a construct or delivery system demonstrates validated post-delivery output control within predefined pharmacokinetic and pharmacodynamic limits. This is a pharmacological boundary, not a delivery obstacle. We conclude that the greatest advances in mRNA 2.0 will come not from delivery alone but from disciplined indication triage by class.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080941","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:55:11Z","timestamp":1785419711000},"page":"941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Two Classes of Protein Therapeutics: Why Dose\u2013Response Architecture Defines the Boundary of mRNA Medicines"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0513-0336","authenticated-orcid":false,"given":"Sarfaraz K.","family":"Niazi","sequence":"first","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1126\/science.1690918","article-title":"Direct gene transfer into mouse muscle in vivo","volume":"247","author":"Wolff","year":"1990","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1126\/science.1546298","article-title":"Reversal of diabetes insipidus in Brattleboro rats: Intrahypothalamic injection of vasopressin mRNA","volume":"255","author":"Jirikowski","year":"1992","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. 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