Hypoxia-sensitive macrocycle inclusion complexes for targeted protein degradation.

PROteolysis TArgeting Chimeras (PROTACs) have gained significant attention for targeted protein degradation in cancer therapy. However, their clinical application is limited by low bioavailability, poor tumor distribution, and potential off-target effects. This study presents NaC4A-PROTACs, a hypoxia-responsive host-guest drug delivery system where azo-modified calixarene derivative (Naph-SAC4A) acts as the host molecule, encapsulating PROTAC molecules as the guest.

Integrating Proteolysis-Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation.

Targeted protein degradation (TPD) using the proteolysis-targeting chimeras (PROTACs) is emerging as a revolutionary technology, offering a potential strategy for cancer treatment by inducing the degradation of overexpressed oncogenic proteins in tumors. PROTACs function by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway (UPS) to catalyze the degradation of target oncogenic proteins. Compared to traditional small molecules inhibitors, PROTACs exhibit enhanced selectivity, the ability to overcome drug resistance, and target proteins traditionally deemed "undruggable".

BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy.

The targeted protein degradation (TPD) strategy modulates tumor growth pathways by degrading proteins of interest (POIs) and has reshaped anti-tumor drug research and development. Recently, the emergence of photodegradation-targeting chimeras (PDTACs) and laser irradiation at specific sites enables precise spatiotemporal controllability of TPD. Capitalizing on the advances of PDTACs, herein, we report a nanoplatform for efficiently delivering PDTAC molecule for photodegradation of bromodomain-containing protein 4 (BRD4) proteins, the key activators of oncogenic transcription.

Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.

Hypoxic tumors present a significant challenge in cancer therapy due to their ability to adaptation in low-oxygen environments, which supports tumor survival and resistance to treatment. Enhanced mitophagy, the selective degradation of mitochondria by autophagy, is a crucial mechanism that helps sustain cellular homeostasis in hypoxic tumors. In this study, we develop an azocalix[4]arene-modified supramolecular albumin nanoparticle, that co-delivers hydroxychloroquine and a mitochondria-targeting photosensitizer, designed to induce cascaded oxidative stress by regulating mitophagy for the treatment of hypoxic tumors.

Rapidly separating dissolving microneedles with sustained-release colchicine and stabilized uricase for simplified long-term gout management.

Despite growing prevalence and incidence, the management of gout remains suboptimal. The intermittent nature of the gout makes the long-term urate-lowering therapy (ULT) particularly important for gout management. However, patients are reluctant to take medication day after day to manage incurable occasional gout flares, and suffer from possible long-term toxicity.