Breaking Isolation to Form New Networks: pH-Triggered Changes in Connectivity inside Lipid Nanoparticles

Abstract

There is a growing demand to develop smart nanomaterials that are structure-responsive as they have the potential to offer enhanced dose, temporal and spatial control of compounds and chemical processes. The naturally occurring pH gradients found throughout the body make pH an attractive stimulus for guiding the response of a nanocarrier to specific locations or (sub)­cellular compartments in the body. Here we have engineered highly sensitive lyotropic liquid crystalline nanoparticles that reversibly respond to changes in pH by altering the connectivity within their structure at physiological temperatures. At pH 7.4, the nanoparticles have an internal structure consisting of discontinuous inverse micellar “aqueous pockets” based on space group Fd3m. When the pH is ≤6, the nanoparticles change from a compartmentalized to an accessible porous internal structure based on a 2D inverse hexagonal phase (plane group p6mm). We validate the internal symmetry of the nanoparticles using small-angle X-ray scattering and cryogenic transmission electron microscopy. The high-resolution electron microscopy images obtained have allowed us for the first time to directly visualize the internal structure of the Fd3m nanoparticles and resolve the two different-sized inverse micelles that make up the structural motif within the Fd3m unit cell, which upon structural analysis reveal excellent agreement with theoretical geometrical models.

Multiple Routes to Bicontinuous Cubic Liquid Crystal Phases Discovered by High-Throughput Self-Assembly Screening of Multi-Tail Lipidoids

“…Moreover, such switchable LC morphologies are often sought for delivery-based applications whereby dramatic changes in domain connectivity alter the diffusivity of encapsulated molecules within the liquid crystal. [68][69][70][71] However, further investigation into these applications is beyond the scope of the present manuscript.…”

A microfluidic platform for the controlled synthesis of higher-order liquid crystalline nanoparticles

“…Some literature examples explore cryo-EM of LLC particles formed from various compositions and served as reference points against which our data were compared. 33,34 This allowed complementary phase assignment and estimation of lattice parameters, later validated by SAXS. 33 Samples were concentrated for cryo-EM analysis using centrifugal filters with 30 kDa pores for 10 minutes at 10 k r.c.f.…”

Photoluminescent polymer cubosomes prepared by RAFT-mediated polymerization-induced self-assembly

“…5,6 In particular, cubosomes and hexosomes that are responsive to the environment or possess photoluminescent properties may find more potential applications such as for diagnostic devices and bioimaging agents. [7][8][9] However, the inability to adjust the pore and channel sizes of lipid-based cubosomes and hexosomes greatly limits their use for loading large molecules such as proteins, RNAs, and others. 4 In the last few years, cubosomes and hexosomes prepared from amphiphilic block copolymers with larger lattice parameters (30-60 nm) have emerged as new alternatives to conventional lipid particles and have found new applications in templating, separation, catalysis and photonics.…”

“…5,6 In particular, cubosomes and hexosomes that are responsive to the environment or possess photoluminescent properties may find more potential applications such as for diagnostic devices and bioimaging agents. 7–9 However, the inability to adjust the pore and channel sizes of lipid-based cubosomes and hexosomes greatly limits their use for loading large molecules such as proteins, RNAs, and others. 4…”