Tumor Microenvironment-Activatable Nanosystem Capable of Overcoming Multiple Therapeutic Obstacles for Augmenting Immuno/Metal-Ion Therapy

ACS Nano. 2024 Mar 26;18(12):8996-9010. doi: 10.1021/acsnano.3c12745. Epub 2024 Mar 13.

Abstract

Abnormal tumor microenvironment (TME) imposes barriers to nanomedicine penetration into tumors and evolves tumor-supportive nature to provide tumor cell protection, seriously weakening the action of antitumor nanomedicines and posing significant challenges to their development. Here, we engineer a TME-activatable size-switchable core-satellite nanosystem (Mn-TI-Ag@HA) capable of increasing the effective dose of therapeutic agents in deep-seated tumors while reversing tumor-supportive microenvironment for augmenting immuno/metal-ion therapy. When activated by TME, the nanosystem disintegrates, allowing ultrasmall-sized Ag nanoparticles to become unbound and penetrate deep into solid tumors. Simultaneously, the nanosystem produces O2 and releases TGF-β inhibitors in situ to drive macrophage M2-to-M1 polarization, increasing intratumoral H2O2 concentration, and ultimately augmenting metal-ion therapy by accelerating hypertoxic Ag+ production. The nanosystem can overcome multiple obstacles that aid in tumor resistance to nanomedicine, demonstrating effective tumor penetration, TME regulation, and tumor inhibition effects. It can provoke long-term immunological memory effects against tumor rechallenge when combined with immune checkpoint inhibitor anti-PD-1. This work provides a paradigm for designing efficient antitumor nanomedicines.

Keywords: abnormal tumor microenvironment; antitumor nanomedicines; macrophages; penetration; tumor-supportive microenvironment.

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Metal Nanoparticles*
  • Nanoparticles* / therapeutic use
  • Neoplasms* / therapy
  • Silver / pharmacology
  • Tumor Microenvironment

Substances

  • Hydrogen Peroxide
  • Silver