Who Actually Receives the Dose? A Cell-State-Aware Targeting Model for Spatially Heterogeneous Tumor Microenvironments and Treatment-Resistant Cellular Niches

Nanomedicine performance is commonly summarized through administered dose, blood pharmacokinetics, organ biodistribution, or average tumor accumulation. These measurements are essential but cannot establish which vascular, stromal, immune, or malignant-cell states encounter a carrier, internalize it, release its payload, or achieve pharmacologically relevant intracellular exposure. This article develops the proposed Cell-State-Aware Targeting Model as an original non-empirical architecture for representing nanocarrier delivery across spatially heterogeneous tumor microenvironments. The model treats delivery as a sequence of conditional gates encompassing systemic availability, vascular proximity and entry, interstitial transport, cellular contact, receptor accessibility, internalization, intracellular trafficking, payload release, and state-specific biological action. Its primary analytical unit is a cell state at a defined spatial location and time rather than an averaged tumor, lesion, or cell type. Particular attention is given to resistant niches and treatment-induced state transitions that may alter target expression, accessibility, trafficking, or payload sensitivity after therapy begins. Proposed outputs include cell-state active-payload dose, target-state coverage, exposure dispersion, resistant-niche minimum coverage, off-target compartment capture, effective intracellular-delivery fraction, spatial exposure–target concordance, and transition-robust coverage. Validation would require coordinated spatial omics, multiplex imaging, quantitative pathology, carrier-specific localization, intracellular trafficking measurements, payload-state analysis, and functional assays. The framework is intended to organize mechanistic questions, experimental design, and evidence reporting rather than provide validated predictions or clinical treatment rules. Its central boundary is that tumor accumulation, cellular uptake, intracellular release, and therapeutic consequence are related but non-equivalent endpoints whose relationships remain conditional on formulation, disease context, biological state, measurement method, and intended decision use.