# Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility

## TL;DR

Researchers improved red blood cell-derived nanovesicles by adding tumor-targeting molecules, finding that cRGD was most effective for targeting breast cancer while maintaining safety.

## Contribution

Systematic comparison of multiple tumor-targeting ligands on RNVs for breast cancer targeting and biocompatibility.

## Key findings

- RNVs functionalized with cRGD showed highest tumor accumulation and cellular uptake in breast cancer models.
- Engineered RNVs demonstrated robust stability and minimal off-target toxicity in mice.
- Fluorescence imaging confirmed enhanced tumor selectivity of ligand-modified RNVs over unmodified vesicles.

## Abstract

Cell membrane-derived nanovesicles, particularly those originating from red blood cells (RNVs), have garnered considerable attention as innovative drug delivery vehicles in oncology, owing to their exceptional biocompatibility, immune evasion, and prolonged systemic circulation. Nevertheless, their inherently poor tumor-targeting efficiency and nonspecific biodistribution present major obstacles to their therapeutic translation.

This study sought to functionalize RNVs with a diverse array of tumor-targeting ligands – cRGD, transferrin (TRF), folic acid (FA), GE11, and RVG29 – and to systematically compare their tumor-homing efficiency, biodistribution, and biosafety in a breast cancer model.

Functionalized RNVs exhibited markedly enhanced tumor affinity relative to unmodified vesicles in both in vitro and in vivo settings. Among the engineered formulations, RNV@cRGD achieved the most pronounced intratumoral accumulation and cellular uptake, followed sequentially by RNV@GE11, RNV@TRF, RNV@FA, and RNV@RVG29. Fluorescence imaging corroborated the superior tumor selectivity of engineered constructs, all of which also demonstrated robust stability and negligible off-target toxicity in murine models.

This work presents systematic comparative evaluation of ligand-engineered RNVs, underscoring cRGD as the most potent targeting moiety for breast cancer. These findings illuminate critical design principles for the rational development of tumor-directed RNV-based drug delivery systems and strengthen the translational promise of biomimetic nanocarriers for clinical oncology.