Cancer treatment and pharmaceutical development require targeted treatment and less toxic therapeutic intervention to achieve real progress against this disease. In this scenario, nanomedicine emerged as a reliable tool to improve drug pharmacokinetics and to translate to the clinical biologics based on large molecules. However, the ability of our body to recognize foreign objects together with carrier transport heterogeneity derived from the combination of particle physical and chemical properties, payload and surface modification, make the designing of effective carriers very difficult. In this scenario, physiologically based pharmacokinetic modeling can help to design the particles and eventually predict their ability to reach the target and treat the tumor. This effort is performed by scientists with specific expertise and skills and familiarity with artificial intelligence tools such as advanced software that are not usually in the “cords” of traditional medical or material researchers. The goal of this review was to highlight the advantages that computational modeling could provide to nanomedicine and bring together scientists with different background by portraying in the most simple way the work of computational developers through the description of the tools that they use to predict nanoparticle transport and tumor targeting in our body.

Proteolytic activity is pivotal in maintaining cell homeostasis and function. In pathological conditions such as cancer, it covers a key role in tumor cell viability, spreading to distant organs, and response to the treatment. Endosomes represent one of the major sites of cellular proteolytic activity and very often represent the final destination of internalized nanoformulations. However, little information about nanoparticle impact on the biology of these organelles is available even though they represent the major location of drug release. In this work, we generated albumin nanoparticles with a different resistance to proteolysis by finely tuning the amount of cross-linker used to stabilize the carriers. After careful characterization of the particles and measurement of their degradation in proteolytic conditions, we determined a relationship between their sensitivity to proteases and their drug delivery properties. These phenomena were characterized by an overall increase in the expression of cathepsin proteases regardless of the different sensitivity of the particles to proteolytic degradation.

The use of nanoparticles has revolutionized drug delivery by enabling targeted and controlled therapeutic release. However, their interactions with intracellular organelles, particularly lysosomes, are not yet fully understood. This study delineates the differential effects of two widely used nanocarriers—mesoporous silica (MSNs) and albumin (ANPs) nanoparticles—on lysosomal biology, with a focus on the expression and activity of cathepsins (CtsB and CtsD), which are key proteases involved in protein degradation and maintaining cellular balance. These two types of nanoparticles, differing in their material and degradability, exhibit distinct behaviors inside the cell. We demonstrate that inorganic MSNs cause significant changes in lysosomal function by altering lysosomal content and cathepsin levels, without triggering lysosomal membrane permeabilization—a typical response to organic particle stress. In contrast, ANPs—which are susceptible to lysosomal cathepsin degradation—induce milder changes in cathepsin expression and maintain lysosomal integrity. Our results highlight that the composition of nanocarriers plays a pivotal role in modulating lysosomal protease activity and maintaining overall cellular homeostasis, highlighting the importance of these parameters in the rational design of drug delivery platforms.

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that uses photosensitizers (PSs) activated by light to produce cytotoxic reactive oxygen species (ROS). Although PDT shows clinical promise, its effectiveness is limited by factors such as insufficient tumor targeting, tumor hypoxia, PS instability, and weak immune responses. Biomimetic nanoparticles (BNPs), which combine natural biological materials like cell membranes with synthetic nanocarriers, have emerged as versatile platforms to overcome these challenges. BNPs improve PDT by enhancing tumor-specific delivery of PSs, relieving hypoxia through oxygen delivery or catalytic oxygen generation, and boosting antitumor immunity by promoting immunogenic cell death and working synergistically with immune checkpoint inhibitors. This review details recent progress in BNP-based strategies for targeted PS delivery, ROS production enhancement, hypoxia modulation, and immune system activation. Additionally, it explores multifunctional and theranostic nanoplatforms, their applications in various cancers, and advances toward clinical use. By integrating targeted delivery, tumor microenvironment modulation, and immunotherapy, BNP-facilitated PDT holds great potential for advancing precise cancer treatments.

This study investigates the enhancement of photodynamic therapy (PDT) efficacy through the encapsulation of platinum phthalocyanine (Pc) in albumin nanoparticles (ANP). Encapsulation of Pc in ANP) significantly enhances its biological effects in photodynamic therapy by increasing cellular uptake through receptor-mediated endocytosis and promoting lysosomal accumulation. This leads to marked lysosomal stress and regulated necrotic cell death pathway, while free Pc causes moderate oxidative stress with reversible apoptosis and autophagy. The enhanced phototoxicity of encapsulated Pc was evident across multiple cancer cell lines, especially aggressive phenotypes, whereas resistant lines showed lower sensitivity likely due to efficient ROS scavenging. Despite improved initial uptake, rapid lysosomal release and extracellular extrusion of Pc limit long-term intracellular retention. Morphological and gene expression analyses confirmed distinct cell death mechanisms between free and encapsulated Pc, underscoring the critical role of nanocarrier-mediated delivery in modulating oxidative stress and cellular response. These findings highlight the importance of nanoparticle design in optimizing PDT efficacy by effectively triggering necrotic cell death pathway.