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Nanobody-Targeted Conditional Antimicrobial Therapeutics.

Chayanon Ngambenjawong1,2,3, Henry Ko1,2, Tahoura Samad1,2

  • 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

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Summary
This summary is machine-generated.

Targeting nanobodies enhance conditional therapeutics by improving protease activation at infection sites. This strategy optimizes delivery for antimicrobial peptides and proteins, offering a framework for treating protease-dysregulated diseases.

Keywords:
ADAM10Ly6G/Cbacterial infectionconditional therapeuticconjugatenanobodyprotease

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Area of Science:

  • Biotechnology
  • Drug Delivery
  • Nanomedicine

Background:

  • Conditional therapeutics offer targeted drug delivery by activating in specific disease microenvironments.
  • Protease activity is a common trigger for conditional therapeutics due to its dysregulation in various diseases.
  • Optimizing protease activation for therapeutic cargo remains a challenge.

Purpose of the Study:

  • To design nanobody-targeted conditional antimicrobial therapeutics for bacterial infections.
  • To explore parameters influencing proteolytic activation of therapeutic cargos.
  • To demonstrate the role of active targeting in enhancing conditional therapeutic activation.

Main Methods:

  • Designed nanobody-targeted conditional antimicrobial therapeutics.
  • Delivered model therapeutic peptide and protein to bacterial infection sites.
  • Investigated parameters influencing proteolytic activation, including nanobody pairing with cleavable linkers (e.g., ADAM10-cleavable).

Main Results:

  • Nanobody targeting significantly enhanced therapeutic activation, even with optimized linkers.
  • Pairing Ly6G/C or ADAM10-targeting nanobodies with ADAM10-cleavable linkers improved activation via proximity-enabled reactivity.
  • Demonstrated a distinct role for active targeting in conditional therapeutic activation.

Conclusions:

  • Nanobody-targeted conditional therapeutics improve activation and delivery to infection sites.
  • Active targeting is crucial for optimizing conditional therapeutics in protease-dysregulated diseases.
  • This framework guides the development of advanced conditional therapeutics for various medical conditions.