Opportunities for nanomaterials in enzyme therapy.

In recent years, enzyme therapy strategies have rapidly evolved to catalyze essential biochemical reactions with therapeutic potential. These approaches hold particular promise in addressing rare genetic disorders, cancer treatment, neurodegenerative conditions, wound healing, inflammation management, and infectious disease control, among others. There are several primary reasons for the utilization of enzymes as therapeutics: their substrate specificity, their biological compatibility, and their ability to generate a high number of product molecules per enzyme unit. These features have encouraged their application in enzyme replacement therapy where the enzyme serves as the therapeutic agent to rectify abnormal metabolic and physiological processes, enzyme prodrug therapy where the enzyme initiates a clinical effect by activating prodrugs, and enzyme dynamic or starving therapy where the enzyme acts upon host substrate molecules. Currently, there are >20 commercialized products based on therapeutic enzymes, but approval rates are considerably lower than other biologicals. This has stimulated nanobiotechnology in the last years to develop nanoparticle-based solutions that integrate therapeutic enzymes. This approach aims to enhance stability, prevent rapid clearance, reduce immunogenicity, and even enable spatio-temporal activation of the therapeutic catalyst. This comprehensive review delves into emerging trends in the application of therapeutic enzymes, with a particular emphasis on the synergistic opportunities presented by incorporating enzymes into nanomaterials. Such integration holds the promise of enhancing existing therapies or even paving the way for innovative nanotherapeutic approaches.

Remote Activation of Enzyme Nanohybrids for Cancer Prodrug Therapy Controlled by Magnetic Heating.

Herein, we have developed nanohybrids (nHs) to remotely activate a therapeutic enzyme for its use in Directed Enzyme Prodrug Therapy (DEPT). The coencapsulation of magnetic nanoparticles (MNPs) with horseradish peroxidase (HRP) using biomimetic silica as an entrapment matrix was optimized to obtain nanosized hybrids (∼150 nm) for remote activation of the therapeutic enzyme. HRP converts indole-3-acetic acid (3IAA) into peroxylated radicals, whereas MNPs respond to alternating magnetic fields (AMFs) becoming local hotspots. The AMF application triggered an increase in the bioconversion rate of HRP matching the activity displayed at the optimal temperature of the nHs (Topt = 50 °C) without altering the temperature of the reaction media. This showed that enzyme nanoactuation is possible with MNPs even if they are not covalently bound. After an extensive physicochemical/magnetic characterization, the spatial location of each component of the nH was deciphered, and an insulating role of the silica matrix was suggested as critical for introducing remote control over HRP. In vitro assays, using a human pancreatic cancer cell line (MIA PaCa-2), showed that only upon exposure to AMF and in the presence of the prodrug, the enzyme-loaded nHs triggered cell death. Moreover, in vivo experiments showed higher reductions in the tumor volume growth in those animals treated with nHs in the presence of 3IAA when exposed to AMF. Thus, this work demonstrates the feasibility of developing a spatiotemporally controlled DEPT strategy to overcome unwanted off-target effects.

Photonic and magnetic materials for on-demand local drug delivery.

Nanomedicine has been considered a promising tool for biomedical research and clinical practice in the 21st century because of the great impact nanomaterials could have on human health. The generation of new smart nanomaterials, which enable time- and space-controlled drug delivery, improve the limitations of conventional treatments, such as non-specific targeting, poor biodistribution and permeability. These smart nanomaterials can respond to internal biological stimuli (pH, enzyme expression and redox potential) and/or external stimuli (such as temperature, ultrasound, magnetic field and light) to further the precision of therapies. To this end, photonic and magnetic nanoparticles, such as gold, silver and iron oxide, have been used to increase sensitivity and responsiveness to external stimuli. In this review, we aim to report the main and most recent systems that involve photonic or magnetic nanomaterials for external stimulus-responsive drug release. The uniqueness of this review lies in highlighting the versatility of integrating these materials within different carriers. This leads to enhanced performance in terms of in vitro and in vivo efficacy, stability and toxicity. We also point out the current regulatory challenges for the translation of these systems from the bench to the bedside, as well as the yet unresolved matter regarding the standardization of these materials.