by dispersion, suspension emulsion, or miniemulsion polymerization, while the preparation of polymer nanocarriers made from preformed polymers usually occurs by coacervation methods such as salting out, [13] emulsification-diffusion, [14] nanoprecipitation, and supercritical fluid technology. [15,16] Among those different preparation techniques, miniemulsion is particularly attractive due to its ability to prepare nanocarriers from either mono mer or polymer while allowing for the efficient loading of large doses of therapeutic agents, which can be lipophilic and/or hydrophilic compounds. [17] Furthermore, miniemulsion provides the opportunity to finely tune particle size distribution while preparing emulsion with high solid content of polymers. [18][19][20] The crosslinking of polymer-containing nanodroplets formed by miniemulsion is a particularly attractive method to produce nanocarriers (Figure 1). Hollow nanocapsules can be prepared by a polyaddition or polycondensation reaction occurring at the droplets interface. [21] In order to prepare nanocarriers, the polymer is dissolved in a good solvent and emulsified with an immiscible nonsolvent forming the continuous phase. After the emulsification, a crosslinking agent, soluble in the continuous phase, is added to the emulsion and the poly addition or polycondensation reaction between the polymer and crosslinking agent occurs at the surface of the droplet. When the reaction kinetic is fast enough, a shell insoluble in both phases can be formed at the interface. [22] To control the size and size distribution of the nanocapsules prepared by the polyaddition/polycondensation reaction at the droplet interface, it is critical to control the preparation of the miniemulsion used as a precursor. The two main factors leading to the broadening of the size distribution of the nanodroplets during miniemulsion are (i) Ostwald ripening and (ii) coalescence of the droplets occurring through collision. The coalescence could be controlled by the addition of an appropriate surfactant, which provides electrostatic or steric stabilization thus preventing droplet coalescence. Ostwald ripening is affected by multiple factors such as droplet size, Laplace pressure, polydispersity, and solubility of the dispersed phase in the continuous phase. In general, Ostwald ripening could be limited by the addition of compounds increasing the osmotic pressure in the system. These chemicals need to be highly insoluble in the continuous phase but completely soluble in the Nanocapsules Polymer nanocarriers are used as transport modules in the design of the next generation of drug delivery technology. However, the applicability of nanocarrier-based technology depends strongly on our ability to precisely control and reproduce their synthesis on a large scale because their properties and performances are strongly dependent on their size and shape. Fundamental studies and practical applications of polymer nanocarriers are hampered by the difficulty of using the current methods to produce monodispersed ...

Bio-orthogonal reactions have become an essential tool to prepare biomaterials; for example, in the synthesis of nanocarriers, bio-orthogonal chemistry allows circumventing common obstacles related to the encapsulation of delicate payloads or the occurrence of uncontrolled side reactions, which significantly limit the range of potential payloads to encapsulate. Here, we report a new approach to prepare pH-responsive nanocarriers using dynamic bio-orthogonal chemistry. The reaction between a poly(hydrazide) crosslinker and functionalized polysaccharides was used to form a pH-responsive hydrazone network. The network formation occurred at the interface of aqueous nanodroplets in miniemulsion and led to the production of nanocapsules that were able to encapsulate payloads of different molecular weights. The resulting nanocapsules displayed low cytotoxicity and were able to release the encapsulated payload, in a controlled manner, under mildly acidic conditions.

Responsive nanogel systems are interesting for the drug delivery of bioactive molecules due to their high stability in aqueous media. The development of nanogels that are able to respond to biochemical cues and compatible with the encapsulation and the release of large and sensitive payloads remains challenging. Here, multistimuli-responsive nanogels were synthesized using a bio-orthogonal and reversible reaction and were designed for the selective release of encapsulated cargos in a spatiotemporally controlled manner. The nanogels were composed of a functionalized polysaccharide cross-linked with pH-responsive hydrazone linkages. The effect of the pH value of the environment on the nanogels was fully reversible, leading to a reversible control of the release of the payloads and a “stop-and-go” release profile. In addition to the pH-sensitive nature of the hydrazone network, the dextran backbone can be degraded through enzymatic cleavage. Furthermore, the cross-linkers were designed to be responsive to oxidoreductive cues. Disulfide groups, responsive to reducing environments, and thioketal groups, responsive to oxidative environments, were integrated into the nanogel network. The release of model payloads was investigated in response to changes in the pH value of the environment or to the presence of reducing or oxidizing agents.