Enzyme-responsive nanomaterials for controlled drug delivery

Abstract

Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials used for controlled drug release have achieved significant development and have been studied as an important class of drug delivery strategies in nanomedicine. In this review, we describe enzymes such as proteases, phospholipases and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area.

Fig. 1

A schematic illustrating typical implementations of enzyme-responsive nanomaterials for controlled drug delivery. (A) Drugs can be directly released from a variety of carriers upon site-specific cleavage by enzymes. (B) Drug carriers can be activated by enzymes to expose targeting ligands for the subsequent cellular delivery. (C) Enzymes can facilitate the generation of specific products that result in drug release from carriers.

Fig. 2

(A) Schematic illustration of development and enzyme-responsive mechanism of peptide-grafted polymers. (B) Luciferase activity in tumor site 24 h after intratumoral injection of peptide-grafted polymers 1 or 2 (C/A = 2.0). Arrows and circles indicate the site of xenografted-tumor tissue. Reproduced from ref. 40 with permission from American Chemical Society.

Fig. 3

Schematic illustration of activatable CPPs. The enzyme-responsive inhibitory domain can be dissociated at cleavable site, resulting in the internalization of nanoparticles. Reproduced from ref. 45 with permission from the National Academy of Sciences.

Fig. 4

Schematic illustration of the mechanism of prodrug based liposome which could be hydrolyzed by sPLA₂ to release the drug after cyclization. Reproduced from ref. 56 with permission from WILEY.

Fig. 5

Injectable glucose-responsive nano-network for insulin delivery. (a) Ketal modified dextran-based nanoparticle encapsulated with insulin, Gox and catalase. (b) Decoration of nanoparticles with chitosan and alginate, respectively. (c) Formation of Nano-network (NN) via electrostatic interaction and dissociation via the catalytic conversion of glucose into gluconic acid (d) Schematic of glucose-responsive insulin delivery for type 1 diabetes treatment using the STZ-induced diabetic mice model. Reproduced from ref. 5 with permission from American Chemical Society.

Fig. 6

(A) Schematic of preparation and enzyme-responsive mechanism of a smart micellar nanocarrier. Reproduced from ref. 60 with permission from American Chemical Society. (B) Schematic representation of the disruption of PEG-N=N-PS block copolymer based micellar in the presence of azoreductase. Reproduced from ref. 61 with permission from American Chemical Society.

Fig. 7

(A) Schematic illustration of size change of QDGelNPs and release of 10-nm QD NPs in the presence of MMP-2. (B) GFC chromatograms of QDGelNPs after incubation with MMP-2. Reproduced from ref. 69 with permission from the National Academy of Sciences. (C) Retention of enzyme-responsive nanoparticles in HT-1080 tumors after intratumoral injection. Reproduced from ref. 70 with permission from American Chemical Society.

Fig. 8

Schematic illustration of preparation and mechanism of protein nanocapsules. (A) Preparation of protein nanocapsules via in situ polymerization. (B) Typical monomers and cross-linker used in enzyme-responsive nanocapsule system. Reproduced from ref. 71 with permission from American Chemical Society.

Fig. 9

Scheme of of the enzyme-responsive liposome for the tumor cell-specific delivery of adenoviral vectors. Reproduced from ref. 81 with permission from Elsevier.

Fig. 10

Schematic illustration of mechanism of core–shell-based Gel–Liposome for programmed and site-specific drug delivery. Reproduced from ref. 86 with permission from WILEY.

Fig. 11

Si-MPs-based enzyme-responsive drug delivery system. (A) Schematic illustration of Si-MP-CD. (B) FE-SEM image of Si-MP-CD. (C) Functional ligand on the surface of SiMP-NBE-CD. (D) α-amylase and lipase triggered release of guest molecules from Si-MP-CD. Reproduced from ref. 89 with permission from American Chemical Society.

Fig. 12

Schematic illustration of enzyme-cleavable DEVD peptide-conjugated gold nanoparticles (DEVD-AuNPs). Reproduced from ref. 92 with permission from American Chemical Society.

Fig. 13

Enzyme-based dual responsive drug delivery system. (A) Schematic illustration of design of CPX1 and CPX2. Reproduced from ref. 95 with permission from Elsevier. (B) Release of cargoes from temperature/enzyme dual-responvie MSPs. Reproduced from ref. 96 with permission from WILEY.