Near-Infrared-Activatable PROTAC Nanocages for Controllable Target Protein Degradation and On-Demand Antitumor Therapy

Abstract

As a novel protein knockdown tool, proteolysis targeting chimeras (PROTACs) can induce potent degradation of target proteins by hijacking E3 ubiquitin ligases. However, the uncontrollable protein disruption of PROTACs is prone to cause “off-target” toxicity after systemic administration. Herein, we designed a photocaged-PROTAC (phoBET1) and loaded it in UCNPs-based mesoporous silica nanoparticles (UMSNs) to construct a NIR light-activatable PROTAC nanocage (UMSNs@phoBET1) for controllable target protein degradation. Upon NIR light (980 nm) irradiation, UMSNs@phoBET1 nanocages could be activated to release active PROTAC via a controlled pattern for degrading bromodomain-containing protein 4 (BRD4) and inducing MV-4-11 cancer cell apoptosis. In vivo experiments demonstrated that UMSNs@phoBET1 nanocages were capable of responding to NIR light in tumor tissues to achieve BRD4 degradation and effectively suppress tumor growth. This NIR light-activatable PROTAC nanoplatform compensates for the current shortcomings of short-wavelength light-controlled PROTACs and presents a paradigm for the precise regulation of PROTACs in living tissues.

Nano-PROTACs: state of the art and perspectives

“…Based on this strategy, light-controllable PROTAC prodrug nanoparticles to address the on-target off-tissue toxicity of PROTACs have recently been reported to spatiotemporally activate and release PROTACs. 14,29–33 Briefly, PROTAC molecules are modified with responsive fragments with photo-caged groups to release PROTACs upon certain irradiation, accompanied by the de-caging and subsequent self-immolated cleavage of versatile responsive linkers (Fig. 2A).…”

“…In addition to gold nanoparticles, other inorganic nanomaterials such as mesoporous silica nanoparticles 32,43 have also attracted considerable attention for PROTAC delivery with favorable pharmacokinetic properties. He and co-workers prepared photo-caged PROTAC-loaded mesoporous silica nanoparticles (phoBET1) for controllably targeted BRD4 degradation (Fig.…”

Designer Nanoreactors for Bioorthogonal Catalysis

“…NRs equipped with nanoprobes (such as plasmonic NPs or quantum dots), for target-responsive colorimetric or photoluminescence emission/quenchingbased optical read-out capabilities, should be developed. d) Cellular f unction monitoring and modulation: 54 To monitor and modulate biochemical functions within living cells, such as biochemical signaling and cell−cell communication, for potential applications in cell-based therapeutics. Also, enabling NRs to precisely sense and modulate the chemical identity of different organelles, membranes, or cytoplasmic regions.…”

“…NRs with open-mouth cavities or macropores, where large-size biomolecules can easily approach the catalytic sites, will be useful. Nanobioreporters : Designing NRs with specific reaction-dependent sensing capabilities for subcellular proteomics, enabling real-time identification of proteins as potential disease biomarkers or indicators of specific physiological conditions. NRs equipped with nanoprobes (such as plasmonic NPs or quantum dots), for target-responsive colorimetric or photoluminescence emission/quenching-based optical read-out capabilities, should be developed. Cellular function monitoring and modulation : To monitor and modulate biochemical functions within living cells, such as biochemical signaling and cell–cell communication, for potential applications in cell-based therapeutics. Also, enabling NRs to precisely sense and modulate the chemical identity of different organelles, membranes, or cytoplasmic regions.…”

“…Cellular function monitoring and modulation : To monitor and modulate biochemical functions within living cells, such as biochemical signaling and cell–cell communication, for potential applications in cell-based therapeutics. Also, enabling NRs to precisely sense and modulate the chemical identity of different organelles, membranes, or cytoplasmic regions.…”