A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

The complex tumor microenvironment constitutes a variety of barriers to prevent nanoparticles (NPs) delivery and results in extremely low accumulation of nanomedicines in solid tumors. Here, a newly developed size‐changeable collagenase‐modified polymer micelle is employed to enhance the penetration and retention of nanomedicine in deep tumor tissue. The TCPPB micelle is first formed by self‐assembly of maleimide‐terminated poly(ethylene glycol)‐block‐poly(β‐amino ester) (MAL‐PEG‐PBAE) and succinic anhydride‐modified cisplatin‐conjugated poly(ε‐caprolactone)‐block‐poly(ethylene oxide)‐triphenylphosphonium (CDDP‐PCL‐PEO‐TPP). Next, Col‐TCPPB NPs are prepared through a “click” chemical combination of thiolated collagenase and maleimide groups on TCPPB micelle. Finally, biocompatible chondroitin sulfate (CS) is coated to obtain CS/Col‐TCPPB NPs for avoiding collagenase inactivation in blood circulation. In tumor acidic microenvironment, the hydrophobic PBAE segments of the resultant micelles become hydrophilic, leading to a dissociation and subsequent dissolution of partial collagenase‐containing components (Col‐PEG‐PBAE) from NPs. The dissolved Col‐PEG‐PBAE promotes the digestion of collagen fibers in tumor tissue like a scavenger, which enhances the NPs penetration. Simultaneously, the increased hydrophilicity of residual Col‐PEG‐PBAE in the micellar matrix causes an expansion of the NPs, resulting in an enhanced intratumoral retention. In tumor cells, the NPs target to release the cisplatin drugs into mitochondria, achieving an excellent anticancer efficacy. A size‐changeable collagenase‐modified nanoscavenger is successfully developed, in which the collagenase‐containing components change from hydrophobic to hydrophilic in an acidic tumor microenvironment. Some of the components dissolve into deep tumor tissues to clear the barriers of nanoparticle (NP) delivery, enhancing the penetration of the NPs; the others cause the an increase of the NPs' size, resulting in an enhanced intratumoral retention.