Cancer Stem‐Like Cells‐Oriented Surface Self‐Assembly to Conquer Radioresistance

Abstract Cancer stem‐like cells (CSCs), capable of indefinite self‐renewal and differentiation, are considered to be the root cause of tumor radiotherapy (RT) resistance. However, the CSCs‐targeted therapy still remains to be a great challenge because they are commonly located in the deep tumor making drugs hard to approach, and their hypoxic and acidic niche can further aggravate radioresistance. Herein, based on the finding that hypoxic CSCs highly express carbonic anhydrase IX (CAIX) on the cell membrane, a CAIX‐targeted induced in situ self‐assembly system on the surface of CSC is reported to overcome hypoxic CSC‐mediated radioresistance. Via the sequential processes of “monomer release‐target accumulation‐surface self‐assembly”, the constructed peptide‐based drug delivery system (CA‐Pt) exhibits the advantages of deep penetration, amplified CAIX inhibition, and enhanced cellular uptake, which greatly relieves the hypoxic and acidic microenvironment to promote the hypoxic CSC differentiation and combines with platinum to boost the RT‐inducing DNA damage. In both lung cancer tumor mouse and zebrafish embryo models, CA‐Pt treatment can effectively assist RT in suppressing tumor growth and preventing tumor invasion and metastasis. This study uses a surface‐induced self‐assembly strategy to differentiate hypoxic CSCs, which may provide a universal treatment strategy for overcoming tumor radioresistance.