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Abstract <p>Doxycycline (DOXY) is a well-established antibiotic that has recently shown potential in inhibiting matrix metalloproteinase-2 (MMP-2), a key enzyme involved in the progression of abdominal aortic aneurysms (AAA). However, the controlled delivery of DOXY to the aneurysm site, with sustained release and minimal systemic exposure, remains a critical challenge in therapeutic development. To address this, we developed a targeted drug delivery platform based on polymeric nanoparticles (NPs), prepared from water-in-oil-in-water nano-emulsions, encapsulating DOXY and are covalently attached to electrospun ε-poly(caprolactone) (ε-PCL) microfibers. This system was designed to enable local, sustained drug release in the inner wall of aorta while preserving the mechanical properties of the aortic wall. The ε-PCL electrospun microfibers from the patch were first functionalized using oxygen cold plasma treatment, creating free radicals that enabled covalent bonding with chemical groups on the outer layer of DOXY-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. This strategy allowed for robust immobilization of the NPs onto the microfibers surface, forming a composite system capable of localized and controlled drug release over time. Unlike traditional delivery approaches, this method ensures site-specific action of DOXY directly at the aneurysmal tissue, minimizing systemic circulation and reducing off-target toxicity. The platform not only provides a stable drug reservoir but also offers intrinsic biomechanical reinforcement, which is critical in AAA condition. This innovative delivery system represents a significant advance in the localized treatment of vascular disorders. It offers a biocompatible, biodegradable, and precisely targeted therapeutic approach, with potential to reduce the need for surgical intervention and limits the adverse effects associated with systemic drug administration.</p> Highlights <p>- Novel polymeric Doxycycline loaded PLGA nanoparticles have been developed and result efficacious within hMMP-2 mitigation and collagen degradation in Abdominal Aortic Aneurysm condition.</p> <p>- Doxycycline loaded polymeric nanoparticles were covalently anchored to ε-Poly(caprolactone) electrospun microfibers via cold plasma-induced radical grafting, enabling sustained drug release for over 12 days.</p> <p>-&#xa0;Doxycycline-loaded nanoparticles released from microfibers efficaciously mitigate hMMP-2 in human in vitro models of Abdominal Aortic Aneurysm.</p> <p>-&#xa0;Doxycycline released from drug-coated electrospun ε-Poly(caprolactone) although efficacious does not allows time-control.</p> Graphical Abstract <p></p>

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Localized doxycycline delivery via polymeric nanoparticles anchored to electrospun PCL microfiber patch for MMP-2 inhibition in abdominal aortic aneurysm

  • 期刊论文

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  • 发表日期：

    2026年1月20日

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  • Carles Bofill-Bonet,
  • Germán Febas,
  • Margalida Artigues,
  • Inés Moreno-Jiménez,
  • Noemí Balà,
  • Jordi Martorell,
  • Salvador Borrós,
  • Cristina Fornaguera

摘要

Abstract

Doxycycline (DOXY) is a well-established antibiotic that has recently shown potential in inhibiting matrix metalloproteinase-2 (MMP-2), a key enzyme involved in the progression of abdominal aortic aneurysms (AAA). However, the controlled delivery of DOXY to the aneurysm site, with sustained release and minimal systemic exposure, remains a critical challenge in therapeutic development. To address this, we developed a targeted drug delivery platform based on polymeric nanoparticles (NPs), prepared from water-in-oil-in-water nano-emulsions, encapsulating DOXY and are covalently attached to electrospun ε-poly(caprolactone) (ε-PCL) microfibers. This system was designed to enable local, sustained drug release in the inner wall of aorta while preserving the mechanical properties of the aortic wall. The ε-PCL electrospun microfibers from the patch were first functionalized using oxygen cold plasma treatment, creating free radicals that enabled covalent bonding with chemical groups on the outer layer of DOXY-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. This strategy allowed for robust immobilization of the NPs onto the microfibers surface, forming a composite system capable of localized and controlled drug release over time. Unlike traditional delivery approaches, this method ensures site-specific action of DOXY directly at the aneurysmal tissue, minimizing systemic circulation and reducing off-target toxicity. The platform not only provides a stable drug reservoir but also offers intrinsic biomechanical reinforcement, which is critical in AAA condition. This innovative delivery system represents a significant advance in the localized treatment of vascular disorders. It offers a biocompatible, biodegradable, and precisely targeted therapeutic approach, with potential to reduce the need for surgical intervention and limits the adverse effects associated with systemic drug administration.

Highlights

- Novel polymeric Doxycycline loaded PLGA nanoparticles have been developed and result efficacious within hMMP-2 mitigation and collagen degradation in Abdominal Aortic Aneurysm condition.

- Doxycycline loaded polymeric nanoparticles were covalently anchored to ε-Poly(caprolactone) electrospun microfibers via cold plasma-induced radical grafting, enabling sustained drug release for over 12 days.

- Doxycycline-loaded nanoparticles released from microfibers efficaciously mitigate hMMP-2 in human in vitro models of Abdominal Aortic Aneurysm.

- Doxycycline released from drug-coated electrospun ε-Poly(caprolactone) although efficacious does not allows time-control.

Graphical Abstract