A Three‐In‐One Assembled Nanoparticle Containing Peptide–Radio‐Sensitizer Conjugate and TLR7/8 Agonist Can Initiate the Cancer‐Immunity Cycle to Trigger Antitumor Immune Response

Abstract

Radiotherapy (RT) has been shown to cause immunogenic cell death (ICD) of cancer cells, which promote the release of tumor‐associated antigens, and trigger the cancer‐immunity cycle (CIC). However, ICD induced by RT usually does not occur in hypoxic tumor cells due to their resistance to radiation. Moreover, RT also induces programmed death ligand 1 (PD‐L1) upregulation on tumor cells, which has an inhibitory effect on T lymphocytes. Therefore, therapy based on CIC must selectively target the restricted steps of antitumor immunity. Herein, the authors design a versatile three‐in‐one assembling nanoparticle that can simultaneously execute these obstacles. The amphiphilic peptide drug conjugate NIA‐D1, containing the hydrophobic radio‐sensitizer 2‐(2‐nitroimidazol‐1‐yl) acetic acid (NIA), a peptide substrate of matrix metalloproteinase‐2, and a hydrophilic PD‐L1 antagonist DPPA‐1, is constructed and co‐assembled with hydrophobic Toll‐like receptor (TLR) 7/8 agonist R848 to form nanoparticle NIA‐D1@R848. The NIA‐D1@R848 nanoparticles combined with RT can trigger the apoptosis of tumor cells and initiate the CIC. In the presence of R848, it promotes the maturation of dendritic cells, which together with protein programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 blockade to relieve T cell suppression, and amplify the antitumor immune cycle. In conclusion, a functionalized three‐in‐one nanoparticle NIA‐D1@R848 is successfully constructed, which can induce strong systemic antitumor immune response.

A Vanadium-Based Nanoplatform Synergizing Ferroptotic-like Therapy with Glucose Metabolism Intervention for Enhanced Cancer Cell Death and Antitumor Immunity

“…To evaluate the MMP-2-responsive detachment potential of PPA, FITC-labeled PPA ( FITC PPA) was used to prepare FITC PMVL; and the extent of FITC PPA detachment could be reflected by the changes in the fluorescence intensity of FITC in the supernatant after centrifugation (16000 rpm, 20 min). , Figure G shows that the fluorescence intensity of FITC PMVL decreased with prolonged MMP-2 incubation time, verifying the time-dependent detachment of FITC PPA from FITC PMVL. This MMP-2 sensitive detachment of PPA enabled it to be released in response to the overexpressed MMP-2 in the TME and to interfere with the PD-1/PD-L1 recognition between CTLs and tumor cells.…”

“…Briefly, FITC PMVL was incubated in PBS containing MMP-2 (0.1 μg mL −1 ). 49 Then the mixed solution was centrifuged (16000 rpm, 20 min) and rinsed three times to thoroughly dislodge the detached FITC PPA. The precipitate of FITC PMVL was redispersed in PBS, the fluorescence intensity of which was measured via a multimode plate reader (EnSight, Singapore).…”

“…FITC-labeled PPA ( FITC PPA) was used instead of PPA to prepare FITC-labeled PMVL ( FITC PMVL). Briefly, FITC PMVL was incubated in PBS containing MMP-2 (0.1 μg mL –1 ) . Then the mixed solution was centrifuged (16000 rpm, 20 min) and rinsed three times to thoroughly dislodge the detached FITC PPA.…”

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

“…97,98 Notably, several hydrophobic immunological agents or radiosensitizers, such as cyclic dinucleotides and 2-(2-nitroimidazol-1-yl) acetic acid, can act as the hydrophobic domain in self-assembled polymeric conjugates. 151,152…”

Robust Electrochemical Biosensors Based on Antifouling Peptide Nanoparticles for Protein Quantification in Complex Biofluids

“…Supramolecular chemistry, proposed by Cram and Lehn in 1970s, provides a new direction to construct ordered nanostructures . Peptides can be properly designed to assemble into a variety of nanostructures, such as nanofibers, nanospheres, and two-dimensional sheets. − To date, peptide-based nanomaterials are usually formed by noncovalent interactions, such as π–π stacking interactions, hydrophobic interactions, ionic interactions, and hydrogen bonding . Studies showed that hydrophobic interactions, aromatic interactions, and salt bridge between charge pairs take a vital part in the stability of self-assembled peptides .…”