Size-Transformable amphiphilic dendrimer-based drug Nanomicelles for enhanced tumor penetration in cancer chemotherapy

Nanotechnology-based drug delivery systems (NDDSs) represent a promising paradigm for cancer therapy. Nonetheless, their clinical translation is substantially impeded by the heterogeneous and physiologically complex tumor microenvironment-particularly the limited penetration of therapeutic agents into the deeper stromal and parenchymal compartments of solid tumors-constituting a critical barrier that warrants urgent scientific investigation. We developed a size-transformable nanomicelle drug delivery system (PCAmDM) utilizing amphiphilic dendrimers and PEGylated polymers, employing a modular co-assembly strategy with in situ bioorthogonal chemistry. The PCAmDM nanomicelles achieved a high doxorubicin (DOX) loading efficiency, featuring a PEGylated surface that enhances stability, prolongs blood circulation, and promotes tumor accumulation via the enhanced permeability and retention (EPR) effect. These nanomicelles exhibit pH-responsive size reduction in the acidic tumor microenvironment (TME), releasing smaller nanomicelles to enhance penetration and therapeutic efficacy in various tumor multicellular spheroids. The size-transformable PCAmDM significantly enhances the in vivo therapeutic efficacy of DOX while reducing systemic toxicity in pancreatic xenograft models. These results highlight the significant potential of this TME-responsive, dendrimer-based nanoplatform as a next-generation drug delivery system in precision cancer therapy. Furthermore, it offers a broadly applicable strategy to enhance the clinical use of traditional chemotherapeutics and provides a versatile framework for designing smart nanocarriers with tailored properties for advanced oncology applications. STATEMENT OF SIGNIFICANCE: Nanotechnology-enabled drug delivery systems offer significant therapeutic potential for cancer treatment. However, the effectiveness of current methods is often limited by the heterogeneous tumor microenvironment, especially the poor penetration of therapeutics into deeper tumor regions. To address this key challenge, we developed size-transformable nanomicelles from amphiphilic dendrimers through modular co-assembly and in situ bioorthogonal chemistry. These engineered nanomicelles demonstrate superior features, including high drug loading, prolonged circulation, increased tumor accumulation, and notably, better penetration into deep tumor tissues. As a result, they achieved remarkable therapeutic results in pancreatic xenograft models. This work provides new insights into designing dendrimer-based nanomicelles as a promising platform for deep tumor-penetrating drug delivery in precision cancer therapy.