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Abstract We report noncovalent assemblies of iRGD peptides and methylene blue dyes via electrostatic and hydrophobic stacking. These resulting nanomaterials could bind to cancer cells, image them with photoacoustic signal, and then treat them via photodynamic therapy. We first assessed the optical properties and physical properties of the materials. We then evaluated their utility for live cell targeting, in vivo imaging, and in vivo photodynamic toxicity. We tuned the performance of iRGD by adding aspartic acid (DD) or tryptophan doublets (WW) to the peptide to promote electrostatic or hydrophobic stacking with methylene blue, respectively. The iRGD-DD led to 150-nm branched nanoparticles, but iRGD-WW produced 200-nm nano spheres. The branched particles had an absorbance peak that was redshifted to 720 nm suitable for photoacoustic signal. The nanospheres had a peak at 680 nm similar to monomeric methylene blue. Upon continuous irradiation, the nanospheres and branched nanoparticles led to a 116.62% and 94.82% increase in reactive oxygen species in SKOV-3 cells relative to free methylene blue at isomolar concentrations suggesting photodynamic toxicity. Targeted uptake was validated via competitive inhibition. Finally, we used in vivo bioluminescent signal to monitor tumor burden and the effect of for photodynamic therapy: The nanospheres had little impact versus controls (p = 0.089), but the branched nanoparticles slowed SKOV-3 tumor burden by 75.9% (p < 0.05). 

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.