The recent advancements on membrane protein degraders (MPDs) have broadened the applicability of proteolysis-targeting chimeras (PROTACs) beyond intracellular proteins to include the previously “undruggable” cell-surface targets. However, the potential toxicity of MPDs caused by undesired off-target degradation poses a significant challenge to clinical deployment, mirroring concerns associated with PROTACs. Here, we introduce a conditionally activatable membrane protein degrader (Pro-MPD), which leverages the specificity and high affinity of biparatopic nanobodies combined with a tumor microenvironment-activated cell-penetrating peptide (Pro-CPP) to achieve on-target activated internalization and degradation of PD-L1 within tumor sites. This modularly designed Pro-MPD demonstrated a high target degradation efficiency and T cell reactivation, as well as sustained inhibition of tumor growth in xenograft models, highlighting its potential as a safer and highly efficient MPD for in vivo applications. Our work provides a general strategy for the development of conditionally activatable MPDs, which offers a new avenue for reducing the undesired systemic toxicity of MPDs due to the off-tumor degradation.

Pneumonia is a ubiquitous disease caused by viral and bacterial infections, characterized by high levels of reactive oxygen species in inflamed areas. Therapeutic strategies targeting reactive oxygen species levels in pneumonia have limited success due to the intricate nature of lung tissues and lung inflammatory responses. Here we describe an inhalable, non-invasive therapeutic platform composed of engineered cerium-based tannic acid nanozymes bound to a self-assembling peptide. In vitro and in vivo studies show that the nanozyme is internalized mostly by activated macrophages and

N⁶-methyladenosine (m⁶A)–modified mRNAs and their cytoplasmic reader YTHDFs are colocalized with stress granules (SGs) under stress conditions, but the interplay between m⁶A modification and SG stability remains unclear. Here, we presented a spatiotemporal m⁶A imaging system (SMIS) that can monitor the m⁶A modification and the translation of mRNAs with high specificity and sensitivity in a single live cell. SMIS showed that m⁶A-modified reporter mRNAs dynamically enriched into SGs under arsenite stress and gradually partitioned into the cytosol as SG disassembled. SMIS revealed that knockdown of YTHDF2 contributed to SG disassembly, resulting in the fast redistribution of mRNAs from SGs and rapid recovery of stalled translation. The mechanism is that YTHDF2 can regulate SG stability through the interaction with G3BP1 in m⁶A-modified RNA-dependent manner. Our results suggest a mechanism for the interplay between m⁶A modification and SG through YTHDF2 regulation.

Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicron variants and guides vaccine development for combating the COVID-19 pandemic.