Enantiomeric Virus-Inspired Oncolytic Particles for Efficient Antitumor Immunotherapy

Abstract

Synthesizing biomimetic systems with stereospecific architectures and advanced bioactivity remains an enormous challenge in modern science. To fundamentally eliminate biosafety issues of natural oncolytic viruses, the development of synthetic virus-inspired particles with high oncolytic activity is urgently needed for clinical antitumor treatments. Here, we describe the design and synthesis of enantiomeric virus-inspired particles for efficient oncolytic therapy from homochiral building blocks to stereospecific supramolecular constructions. The L-virus-inspired oncolytic particles (L-VOPs) and D-VOPs possess similar biomimetic nanostructures but mirror-imaged enantiomeric forms. It is important that both L-VOPs and D-VOPs successfully mimic the pharmacological activity of oncolytic viruses, including direct tumor lysis and antitumor immune activation. D-VOPs provide quite better oncolytic efficacy than that of clinical-grade oncolytic agents (LTX-315, IC50 = 53.00 μg mL–1) with more than 5-fold decrease in IC50 value (10.93 μg mL–1) and close to 100% tumor suppression (98.79%) against 4T1 tumor-bearing mice, attributed to the chirality-dependent tumor recognition, interaction, antidegradation, and immunotherapy. This work provides a strategy for the synthesis of stereospecific biomimetic material systems as well as develops an advanced candidate for biomimetic oncolytic agents without biosafety risks.

Systemic Administration with Bacteria-Inspired Nanosystems for Targeted Oncolytic Therapy and Antitumor Immunomodulation

“…Pharmacodynamics activities of bioactive molecules (including peptide/protein drugs and nucleic acid drugs) are often reduced by biospecific degradation and clearance. Therefore, it was predictable that d -stereospecific bacteria-inspired nanosystems would benefit from their inherent resistance to biodegradation for providing long-acting oncolytic activity. , After pretreatment with trypsin for 24 h, the antitumor toxicity of D OBNs was almost unaffected by enzyme degradation, whereas the antitumor activity of L OBNs greatly decreased under the same condition. For instance, pretreatment with trypsin induced a decrease in antitumor activity, with an increase of tumor cell viability from 30.92% to 79.97% with 5 μg/mL L OBNs, suggesting the dispelled oncolytic activity of L OBNs (Figure j).…”