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However, their therapeutic application is often limited by inefficient cellular uptake. In this study, we present the design, synthesis and physicochemical characterisation of cell\u2010penetrating peptide (CPP)\u2010PNA conjugates that target the oncogenic microRNA miRNA\u2010221\u20105p, as well as their preliminary biological evaluation. Anti\u2010miRNA\u2010221\u20105p PNAs functionalised for conjugation with CPPs via Cu(I)\u2010catalysed azide\u2010alkyne cycloaddition (CuAAC) or disulfide\u2010mediated coupling were synthesised using solid\u2010phase peptide synthesis. Circular dichroism and UV\u2010melting analyses confirmed the formation of a stable, sequence\u2010specific PNA\u2010RNA heteroduplex with miRNA\u2010221\u20105p. This demonstrated strong hybridisation and high thermodynamic stability compared to scrambled control sequences. Cell proliferation assays indicated modest but reproducible antiproliferative effects for the CPP\u2010PNA conjugates co\u2010incubated with chloroquine, with no evidence of acute cytotoxicity. These findings emphasise the potential of CPP\u2010PNA systems for the intracellular delivery of antisense agents and highlight the importance of the linker nature in determining their biological performance.<\/jats:p>","DOI":"10.1002\/psc.70129","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:34:38Z","timestamp":1790933678000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis and Biophysical Characterisation of CPP\u2010PNA Conjugates for Targeting Oncogenic microRNA\u2010221"],"prefix":"10.1002","volume":"32","author":[{"given":"Martina","family":"Rotondo","sequence":"first","affiliation":[{"name":"University of Naples Federico II  Naples Italy"},{"name":"Padova Unit Institute of Biomolecular Chemistry of CNR  Padova 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