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<p>Target-specific strategies are essential for the success of modern drug therapy in terms of safety and effectiveness. Thus, drug delivery must extend beyond tissue-level targeting to intracellular targeting, which is the ultimate site of action. Cell-penetrating peptides (CPPs) have therefore emerged as an approach to deliver drugs into target cells, yet concerns remain regarding cytotoxicity and limited targeting precision. In this context, we investigated biodynamers as a new class of pH-responsive CPPs. Biodynamers are dynamic peptide analogs, composed of amino acid-hydrazides together with a hexaethylene glycol-conjugated carbazole dialdehyde monomer. Each monomer is linked through pH-sensitive dynamic covalent bonds. Therefore, under acidic conditions, these polymers undergo structural rearrangements, including changes in molecular weight and conformation, potentially influencing their pH-dependent uptake. We synthesized three biodynamers with varying Lys-to-Arg ratios and evaluated their uptake in A549 and SW480 cells by pH. All biodynamers exhibited significantly higher uptake in acidic media (pH 6.0, HBSS) compared to neutral conditions at pH 7.4. This acid-induced uptake appears to be promoted by the enhanced electrostatic interactions between the biodynamers and the cell membrane, driven by dynamic degradation of the biodynamer under acidic conditions. Such degradation increases the number of terminal amino groups, thereby elevating charge density. Furthermore, circular dichroism results indicate a conformational change is induced under acidic conditions, which likely contributes to the enhanced cellular internalization as seen with conventional CPPs. Collectively, the biodynamers offer insight into a potential strategy to further enhance the selectivity of cell-penetrating agents for drug delivery in acidic disease microenvironments.</p> Graphical Abstract <p></p>

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Evaluation of dynamic peptide nanorods as a unique pH-dependent cell-penetrating agent

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Philipp Sonntag,
  • Mohamed A. M. Kamal,
  • Camilla Passi,
  • Justine Bassil,
  • Brigitta Loretz,
  • Claus-Michael Lehr,
  • Sangeun Lee

摘要

Target-specific strategies are essential for the success of modern drug therapy in terms of safety and effectiveness. Thus, drug delivery must extend beyond tissue-level targeting to intracellular targeting, which is the ultimate site of action. Cell-penetrating peptides (CPPs) have therefore emerged as an approach to deliver drugs into target cells, yet concerns remain regarding cytotoxicity and limited targeting precision. In this context, we investigated biodynamers as a new class of pH-responsive CPPs. Biodynamers are dynamic peptide analogs, composed of amino acid-hydrazides together with a hexaethylene glycol-conjugated carbazole dialdehyde monomer. Each monomer is linked through pH-sensitive dynamic covalent bonds. Therefore, under acidic conditions, these polymers undergo structural rearrangements, including changes in molecular weight and conformation, potentially influencing their pH-dependent uptake. We synthesized three biodynamers with varying Lys-to-Arg ratios and evaluated their uptake in A549 and SW480 cells by pH. All biodynamers exhibited significantly higher uptake in acidic media (pH 6.0, HBSS) compared to neutral conditions at pH 7.4. This acid-induced uptake appears to be promoted by the enhanced electrostatic interactions between the biodynamers and the cell membrane, driven by dynamic degradation of the biodynamer under acidic conditions. Such degradation increases the number of terminal amino groups, thereby elevating charge density. Furthermore, circular dichroism results indicate a conformational change is induced under acidic conditions, which likely contributes to the enhanced cellular internalization as seen with conventional CPPs. Collectively, the biodynamers offer insight into a potential strategy to further enhance the selectivity of cell-penetrating agents for drug delivery in acidic disease microenvironments.

Graphical Abstract