In situ thermosensitive mRNA-loaded hydrogel modulates post-surgery tumor immune microenvironment to prevent recurrence and metastasis.

Abstract

Surgery remains the primary cancer treatment, but postoperative trauma disrupts the local immune microenvironment by altering the critical balance between M1 and M2 macrophages while simultaneously elevating reactive oxygen species (ROS) levels at the surgical site. The critical clinical dilemma in postoperative tumor management lies in achieving re-balancing over macrophage polarization within the post-operative niche - specifically maintaining tumor-suppressing M1 phenotype while permitting necessary wound-healing M2 function. Here, we developed an in situ thermosensitive hydrogel platform capable of co-delivering two nanoparticle systems (BC₁₂D NPs and PPS NPs) to alleviate the immunosuppressive microenvironment. Specifically, CRISPR/Cas9-loaded nanoparticles (BC₁₂D@CRISPR NPs) were incorporated into the hydrogel for addressing the high proportion of M2-type macrophages at the resection site, reprogramming the macrophages with an effective M1/M2 ratio to exert potent antitumor functions. Meanwhile, the PPS nanoparticles were employed for the clearance of ROS at the surgical site, thereby ensuring that the normal wound healing process remained unimpeded. Using an in situ tumor resection model, the synergistic effects of ROS clearance and macrophage repolarization at the postoperative site were leveraged to achieve efficient immune microenvironment modulation.