Skin is the largest and easily accessible organ of the body and therefore can be extensively used as a prominent route of delivery for local and systemic effects. Though it presents a multifunctional barrier between body and surrounding particles, there are chances to deliver therapeutic nanocarrier, particularly in diseased skin. Both for dermal and transdermal drug delivery, the horny layer, i.e., the uppermost layer of the skin serve as the most resistant layer to be crossed and for this purpose, different perforation techniques are used that relatively widen the skin opening and allow the passage of drug (≤ 10 mg) and micromolecules, but this amateur disruption of the skin can be avoided in order to preserve this barrier against cutaneous microbiota by using deformable nanocarriers. In this review, we discuss the nanosized aggregates and microneedle technology for the advanced delivery of vaccines, protein, peptides, nucleic acid, and hormone across the skin.