Modified-Release Pulmonary Delivery Systems for Labile Bioactives: Design, Development, and Applications

Abstract

Pulmonary delivery of bioactives has shown to be a promising route for the treatment of respiratory conditions, however, numerous physiological barriers, such as mucociliary clearance and immune responses, pose significant hurdles to treatment efficacy. These barriers specifically affect labile bioactives such as mRNA, peptides, proteins, and probiotics, which are susceptible to degradation due to the prevailing conditions. Various drug delivery platforms have been developed to address these challenges, including, among others, polymeric nanoparticles, micelles, liposomes, and solid lipid nanoparticles that encapsulate and protect the labile bioactives during formulation and administration, enabling improved bioavailability, sustained release, and enhanced formulation stability, while further modification of these platforms allows for targeted drug delivery. This review explores the advanced drug delivery systems that have been designed to protect and release labile active agents in a controlled and targeted manner to the lung, with a specific focus provided on the physiological barriers to effective pulmonary delivery and the formulation considerations to overcome these challenges. The outlook of this pertinent field of study has additionally been provided, highlighting the significant potential of the pulmonary delivery of labile bioactive agents for the prevention and treatment of a variety of respiratory ailments.

Keywords: mRNA delivery; nanosystems; physiological barriers; probiotics; proteins and peptides; respiratory system.

Figure 2

A graphical representation of (a) the branched airway network of the lungs illustrating the deposition pathways, the various lung regions involved, and (b) the key biological barriers that affect drug absorption, including epithelial barriers, mucociliary clearance, and immune responses in a healthy patient (adapted with permission from Kunda et al. [20], © 2012 Springer Science Business Media and Plaunt et al. [24], © 2022 by the authors. Licensee MDPI, Basel, Switzerland).

Figure 1

A schematic of the various inhalable drug delivery systems utilizing nanocarriers (created with BioRender.com).

Figure 3

Particle size-dependent lung deposition (created with BioRender.com).

Figure 4

Physicochemical factors influencing pulmonary drug delivery.

Figure 5

Schematic representation of pulmonary administration using polymer–drug conjugates (reproduced with permission from Marasini et al. [70], © 2017 Elsevier Ltd., London, UK).

Figure 6

SLNs developed for the delivery of PAP to the lung, scale bar: 30 μm (reproduced with permission from Gaspar et al. [45], © 2016 Elsevier B.V, Amsterdam, Netherlands).

Figure 7

Images of LNP inhalation resulting in selective transfection within the lungs: (a) representative bioluminescent images of isolated organs demonstrate localized luciferase expression specifically in the lungs, and (b) LNP inhalation results in selective transfection within the lungs (reproduced with permission from Kim et al. [83], © 2022 American Chemical Society, Washington, DC, USA).

Figure 8

Schematic representation of how probiotics contribute to lung cancer prevention through three mechanisms (reproduced with permission from Sharma et al. [94], © 2017 Elsevier Ltd., London, UK).