A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis

Abstract

Photodynamic therapy (PDT) is ineffective against deeply seated metastatic tumors due to poor penetration of the excitation light. Herein, we developed a biomimetic nanoreactor (bio-NR) to achieve synergistic chemiexcited photodynamic-starvation therapy against tumor metastasis. Photosensitizers on the hollow mesoporous silica nanoparticles (HMSNs) are excited by chemical energy in situ of the deep metastatic tumor to generate singlet oxygen (¹O₂) for PDT, and glucose oxidase (GOx) catalyzes glucose into hydrogen peroxide (H₂O₂). Remarkably, this process not only blocks the nutrient supply for starvation therapy but also provides H₂O₂ to synergistically enhance PDT. Cancer cell membrane coating endows the nanoparticle with biological properties of homologous adhesion and immune escape. Thus, bio-NRs can effectively convert the glucose into ¹O₂ in metastatic tumors. The excellent therapeutic effects of bio-NRs in vitro and in vivo indicate their great potential for cancer metastasis therapy.

Fig. 1

Schematic illustrations of the process for synthesizing the biomimetic nanoreactor (a), ROS generation based on CRET with glucose consumption with no light excitation (b), and synergetic photodynamic-starvation therapy for metastases (c)

Fig. 2

Characterization of the biomimetic nanoreactor. TEM images of SiO₂-NH₂ (a), dSiO₂ (b), HMSNs (c), HMSNs-NH₂ (d), and HMSNs-GOx-Ce6@CPPO-PFC@C (e). Scale bar in the inset of (c) is 20 nm and others are 50 nm. f Absorption spectra of HMSNs and HMSNs-Ce6. g Fluorescence spectra of HMSNs and HMSNs-Ce6. Hydrodynamic size distributions (h) and zeta potentials (i) of the nanoparticles

Fig. 3

Verification of H₂O₂ and ¹O₂ generation in vitro. a Fluorescence spectra of Cy-O-Eb probe incubated with HMSNs-GOx-Ce6 in the presence or absence of 1 mM glucose. b ESR spectra of TEMPO after incubation with HMSNs-GOx-Ce6 and Fe²⁺ in the presence (red) or absence (black) of glucose. c The pH values of HMSNs-GOx-Ce6 solution in the presence or absence of 1 mM glucose. d Absorption spectra of ABMD incubated with HMSNs-GOx-Ce6@CPPO-PFC/O₂ in the absence or presence of 1 mM glucose

Fig. 4

a Immunofluorescent staining images of HIF-1α in B16-F10 pre-incubated with HMSNs@PFC@C (top) or HMSNs@PFC/O₂@C (bottom) in a hypoxic environment. b CLSM images of B16-F10 cells incubated with Cy-O-Eb and HMSNs-GOx@PFC/O₂@C (top) or HMSNs-GOx@PFC@C (bottom). c Western blots of CD44, CD47, E-Cadherin, EpCAM, and tissue factor. Column 1, B16-F10 cells; column 2, B16-F10 cell membranes; column 3, HMSNs@C. d In vivo imaging of lung with metastatic tumor at 24 h post injection of HMSNs-Ce6@C (left) or HMSNs-Ce6 (right). White arrows point to the lungs. Enzyme-linked immunosorbent assay (ELISA) analysis of IL-6 (e) and IL-12 (f) after the mice were injected with HMSNs-GOx-Ce6@CPPO-PFC@C or HMSNs-GOx-Ce6@CPPO-PFC

Fig. 5

Therapeutic effects of the bio-NRs in vivo. a Schematic illustration of the in vivo therapeutic process. b Macroscopic images of lungs receiving different treatments. From left to right: control, HMSNs-GOx@CPPO-PFC/O₂@C, HMSNs-Ce6@CPPO-PFC/O₂@C, HMSNs-GOx-Ce6@CPPO-PFC@C, and HMSNs-GOx-Ce6@CPPO-PFC/O₂@C. c The mass percentage of metastases. Mass percentage of metastases/% = weight of metastatic tumors/weight of normal lung. d Body weight curves of mice with metastatic tumors in each group. e Survival rates for each group after receiving treatments. f H&E staining of lung-bearing metastatic tumors after different treatments (×200, scale bars are 100 μm). T= tumor