The
complete regression of residual tumors after photothermal therapy
(PTT) depends on the activation and recognition of the immune system.
However, the inevitable local inflammation after PTT in residual tumor
recruits abundant abnormal immune cells, especially the tumor-associated
macrophages (TAMs) which further promote immune escape and survival
of the remaining tumor cells, resulting in the tumor recurrence and
progression. To solve this problem, herein we explored biomimetic
nanoparticles carrying repolarization agent of TAMs to remodel the
post-PTT inflammatory microenvironment. The polydopamine nanoparticles
were used simultaneously as photothermal transduction agents to ablate
tumor cells and the delivery vehicles for TMP195 which can repolarize
the M2-like TAMs into an antitumor phenotype. In addition, a biomimetic
decoration of macrophage membrane coating was designed to endow nanoparticles
the ability to actively target the tumor site after PTT mediated by
inflammation-mediated chemotaxis. In the breast tumor model, these
biomimetic nanoparticles with immune-modulating ability significantly
elevated the levels of M1-like TAMs, ultimately resulting in a tumor-elimination
rate of 60%, increased from 10% after PTT. This synergistic treatment
strategy of PTT and TAMs repolarization provides a promising approach
to address the deteriorated tumor microenvironment after PTT and proposes
a more effective way for combinational treatment option in clinic.
During the onset of liver fibrosis, capillarized liver sinusoidal endothelial cells (LSECs) limit substance exchange between the blood and the Disse space, further accelerating hepatic stellate cell (HSCs) activation and fibrosis progression. Limited accessibility of therapeutics to the Disse space is often overlooked and remains a major bottleneck for HSCs‐targeted therapy in liver fibrosis. Here, an integrated systemic strategy for liver fibrosis treatment is reported, utilizing pretreatment with the soluble guanylate cyclase stimulator, riociguat, followed by insulin growth factor 2 receptor‐mediated targeted delivery of the anti‐fibrosis agent, JQ1, via peptide‐nanoparticles (IGNP‐JQ1). The riociguat reversed the liver sinusoid capillarization to maintain a relatively normal LSECs porosity, thus facilitating the transport of IGNP‐JQ1 through the liver sinusoid endothelium wall and enhancing the accumulation of IGNP‐JQ1 in the Disse space. IGNP‐JQ1 is then selectively taken up by activated HSCs, inhibiting their proliferation and decreasing collagen deposition in the liver. The combined strategy results in significant fibrosis resolution in carbon tetrachloride‐induced fibrotic mice as well as methionine‐choline‐deficient‐diet‐induced nonalcoholic steatohepatitis (NASH) mice. The work highlights the key role of LSECs in therapeutics transport through the liver sinusoid. The strategy of restoring LSECs fenestrae by riociguat represents a promising approach for liver fibrosis treatment.
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