Drug-induced co-assembly of albumin/catalase as smart nano-theranostics for deep intra-tumoral penetration, hypoxia relieve, and synergistic combination therapy

The abnormal tumor microenvironment (TME) featured with hypoxia, acidosis, dense extracellular matrix and increased tumor interstitial fluid pressure is closely related with the resistance of tumors to various therapies. Herein, a unique type of biocompatible nanoscale delivery system is fabricated by utilizing a chemotherapeutic drug, paclitaxel (PTX), to induce co-assembly of catalase and human serum albumin (HSA), the latter of which is pre-modified with chlorine e6 (Ce6), forming smart multifunctional HSA-Ce6-Cat–PTX nanoparticles via a rather simple one-step method. Upon intravenous injection, HSA-Ce6-Cat–PTX nanoparticles show high tumor accumulation and efficient intra-tumoral diffusion, likely owning to their changeable sizes that can maintain large initial sizes (~ 100 nm) during blood circulation and transform into small protein-drug complexes (< 20 nm) within the tumor. Meanwhile, catalase within those nanoparticles could trigger decomposition of endogenic TME H₂O₂ to generate oxygen in-situ so as to relieve tumor hypoxia. This effect together with PTX-induced intra-tumoral perfusion enhancement is able to dramatically modulate TME to favor the anti-tumor effect in the combined photodynamic/chemotherapy with HSA-Ce6-Cat–PTX. Thus, our work presents a simple drug-induced self-assembly strategy to fabricate enzyme-loaded therapeutic albumin nanoparticles for synergistic cancer combination therapy.