The therapeutic efficacy of fluorescence image-guided
tumor surgery and
photodynamic therapy (
PDT) is impaired by the penetration depth limitation, low signal-to-noise ratio of traditional first near-infrared window (NIR I) fluorescence and the hypoxic tumor microenvironment. Here, a "red blood cell-based multimodal probe" was proposed to achieve enhanced
tumor targeting and retention of
fluorescent probes after an
intravenous injection, so that second near-infrared window (NIR II) fluorescence bioimaging-guided complete
tumor resection and high-efficiency
photodynamic therapy could then be realized. Methods: The
hexanoic acid ester-modified
rose bengal (RB-HA), RGD (
Arginine-
Glycine-Aspartic)
peptide and
avidin were covalently coupled onto
amine-modified upconversion nanoparticles (UCNPs) via
EDC/NHS reaction (UCNPs@RB@RGD@
avidin). Afterwards, the complex of ICG with
bovine serum albumin (BSA) was loaded into RBCs through hypotonic dialysis (RBC@ICG). Then, the
membrane proteins of RBC@ICG were biotinylated by
biotin-modified
phospholipids (RBC@ICG@
biotin). Finally, the
RBCp (Red Blood Cell based probe) was obtained by crosslinking UCNPs@RB@RGD@
avidin to RBC@ICG@
biotin through the interaction of
avidin and
biotin. The obtained multimodal
RBCp was extensively characterized, both in vitro and in vivo, including analysis of chemical, physical and fluorescent features, O2 delivery ability,
tumor accumulation, NIR II fluorescence bioimaging ability, photodynamic therapeutic efficiency, and biosafety. Results: The
RBCp experienced efficient
tumor targeting and long
tumor retention for almost 4 h after
intravenous injection, and the superior signal-to-noise ratio at the optimal time window can be used for guiding precise
tumor resection under an 808-nm
laser irradiation to facilitate lymph popliteal
metastasis surgical delineation. Meanwhile, the
RBCp can provide
laser-responsive O2 release to enhance the
PDT efficiency of popliteal
lymph node metastasis under NIR II fluorescence bioimaging guidance. These excellent performances obviously lead to remarkably enhanced synergistic
therapeutic effects of
tumor surgery and metastatic inhibition. Conclusion: The proposed strategy will develop a new platform to increase surgical resection completeness and improve
PDT efficiency, resulting in the successful and complete inhibition of
tumor and
metastasis, which could offer a promising approach for the clinical translation of malignant
tumor treatment.