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Abstract Tobacco mosaic virus (TMV) was the first virus to be discovered and it is now widely used as a tool for biological research and biotechnology applications. TMV particles can be decorated with functional molecules by genetic engineering or bioconjugation. However, this can destabilize the nanoparticles, and/or multiple rounds of modification may be necessary, reducing product yields and preventing the display of certain cargo molecules. To overcome these challenges, we used phage display technology and biopanning to isolate a TMV‐binding peptide (TBP_T25) with strong binding properties (IC₅₀=0.73 μM, K_D=0.16 μM), allowing the display of model cargos via a single mixing step. The TMV‐binding peptide is specific for TMV but does not recognize free coat proteins and can therefore be used to decorate intact TMV or detect intact TMV particles in crude plant sap. 

Abstract Triggering lysosome‐regulated immunogenic cell death (ICD, e.g., pyroptosis and necroptosis) with nanomedicines is an emerging approach for turning an “immune‐cold” tumor “hot”—a key challenge faced by cancer immunotherapies. Proton sponge such as high‐molecular‐weight branched polyethylenimine (PEI) is excellent at rupturing lysosomes, but its therapeutic application is hindered by uncontrollable toxicity due to fixed charge density and poor understanding of resulted cell death mechanism. Here, a series of proton sponge nano‐assemblies (PSNAs) with self‐assembly controllable surface charge density and cell cytotoxicity are created. Such PSNAs are constructed via low‐molecular‐weight branched PEI covalently bound to self‐assembling peptides carrying tetraphenylethene pyridinium (PyTPE, an aggregation‐induced emission‐based luminogen). Assembly of PEI assisted by the self‐assembling peptide‐PyTPE leads to enhanced surface positive charges and cell cytotoxicity of PSNA. The self‐assembly tendency of PSNAs is further optimized by tuning hydrophilic and hydrophobic components within the peptide, thus resulting in the PSNA with the highest fluorescence, positive surface charge density, cell uptake, and cancer cell cytotoxicity. Systematic cell death mechanistic studies reveal that the lysosome rupturing‐regulated pyroptosis and necroptosis are at least two causes of cell death. Tumor cells undergoing PSNA‐triggered ICD activate immune cells, suggesting the great potential of PSNAs to trigger anticancer immunity.