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 tumour-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 tumours, are not disturbed by functional nanosystems.

The interaction between Pts@DOX/HANGs@Gal and tumours gives rise to Pts activation, achieving the continuous targeted delivery of DOX to tumours, inducing the transition from cold to hot tumours, 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 tumour infiltration of immune cells and deep tumour penetration of the nanosystem.

Consequently, Pts@DOX/HANGs@Gal not only effectively reinforced the antitumor immune response through self-recognised tumour-targeting chemo-immunotherapy and graded drug delivery but also reduced tumour 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 tumour chemo-immunotherapy.

The in vitro and in vivo results collectively demonstrate that the Pts@DOX/HANGs@Gal nanoplatform, not limited by tumour heterogeneity not only possesses excellent tumour 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 remodelled ECM, leading to a promising antitumor effect with prolonged survival time and reduced tumour metastasis.

This study presents promising Pts-based nanovesicles for precise cancer treatment.

Journal: Science Bulletin

Source: Science China Press