Engineered nano-aircraft carrier enhances tumor targeting and immune response

The researchers designed an efficient approach for fabricating engineered Pts-based nano-aircraft carriers with graded drug delivery and ECM degradation for precise cancer chemoimmunotherapy. Briefly, intact Pts without cell nuclei, extracted from tumor-bearing mice, loaded with DOX and served as the mothership (Pts@DOX). Meanwhile, the ECM destroyer HAase was cross-linked with bis-N-hydroxy succinimide (NHS-SS-NHS) to form redox-sensitive nanospheres (HANGs) with the delivery of the immunosuppressant galunisertib (Gal) and acted as a carrier-based aircraft (HANGs@Gal), which was then transplanted onto the surface of the DOX-loaded Pts to form the final Pts-based nano-aircraft carrier Pts@DOX/HANGs@Gal.

The normal physiological features of host Pts, including their excellent targeting capability for both metastatic and orthotopic tumors, are not disturbed by functional nanosystems. The interaction between Pts@DOX/HANGs@Gal and tumors gives rise to Pts activation, achieving the continuous targeted delivery of DOX to tumors, inducing the transition from cold to hot tumors, and promoting the recruitment of immune cells. Simultaneously, the external nanospheres disintegrate from Pts@DOX/HANGs@Gal, releasing galunisertib and hyaluronidase into the extracellular matrix to relieve immune tolerance and open up a high-speed channel for the tumor infiltration of immune cells and deep tumor penetration of the nanosystem. Consequently, Pts@DOX/HANGs@Gal not only effectively reinforced the antitumor immune response through self-recognized tumor-targeting chemo-immunotherapy and graded drug delivery but also reduced tumor metastasis in vivo.

In this study, the team developed an engineered Pts-based nano-aircraft carrier with internally loaded DOX and externally grafted reduction-sensitive HAase-cross-linked nanospheroids loaded with Gal was developed for precise tumor chemo-immunotherapy. The in vitro and in vivo results collectively demonstrate that the Pts@DOX/HANGs@Gal nanoplatform, not limited by tumor heterogeneity not only possesses excellent tumor targeting and precise hierarchical delivery traits, but also effectively reinforces the antitumor immune response and relieves the immunosuppressive microenvironment via the combination of chemotherapy and immunotherapy with a remodeled ECM, leading to a promising antitumor effect with prolonged survival time and reduced tumor metastasis. This study presents promising Pts-based nanovesicles for precise cancer treatment.