A sequentially responsive and structuretransformable nanoparticle with a comprehensively improved ‘CAPIR cascade’ for an enhanced antitumor effect

An intravenously administered drug delivery system should undergo a five-step ‘CAPIR’ cascade (circulation,
accumulation, penetration, internalization and release), and the maximal efficiency of each step is of
great importance to obtain the improved final therapeutic benefits and overall survival rate. Here, a pH/
matrix metalloproteinase-9 (MMP9) sequentially responsive and continuously structure-transformable
nanoparticle assembled from a doxorubicin (DOX)-conjugated peptide was exploited for comprehensively
improving the ‘CAPIR cascade’ and eventually enhancing the therapeutic efficacy. The chimeric peptide
can self-assemble into spherical nanoparticles (RGD-sNPs) at pH 7.4 with a particle size of 45.7 ± 5.4 nm.
By a combination of passive and active targeting mechanisms, RGD-sNPs achieved efficient accumulation
at the tumor site (∼15.1% ID g−1 within 24 h). Both in vitro and in vivo experiments revealed that RGDsNPs
can be transformed into rod-like nanoparticles (S-NFs) triggered by MMP9 that overexpressed in the
tumor microenvironment, demonstrating remarkable advantages of deep tumor penetration, prolonged
drug retention with ∼3.7% ID g−1 at 96 h, and 2-fold enhanced internalization. Subsequently, S-NFs would
respond to the intracellular weakly acidic stimuli to rapidly release DOX for induction of cytotoxicity and
apoptosis. Meanwhile, the remaining peptide was further converted into long fibers (length >5 μm) with
significant cytotoxicity, thereby exerting a synergistic antitumor effect. Thus RGD-sNPs displayed superior
antitumor efficacy and extended the median survival period to 55 days. This provides a new horizon for
the exploration of high-performance antitumor nanomedicines.